CN102939160A - Systems and devices for analysis of samples - Google Patents

Systems and devices for analysis of samples Download PDF

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Publication number
CN102939160A
CN102939160A CN2011800295996A CN201180029599A CN102939160A CN 102939160 A CN102939160 A CN 102939160A CN 2011800295996 A CN2011800295996 A CN 2011800295996A CN 201180029599 A CN201180029599 A CN 201180029599A CN 102939160 A CN102939160 A CN 102939160A
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box
aforementioned
assembly
fluid
passage
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CN2011800295996A
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CN102939160B (en
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文森特·林德
大卫·施泰因米勒
詹森·泰勒
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OPKO Diagnostics LLC
Claros Diagnostics Inc
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Claros Diagnostics Inc
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/02—Mechanical
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2201/06—Illumination; Optics
    • G01N2201/069—Supply of sources
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    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T137/00—Fluid handling
    • Y10T137/0318—Processes
    • Y10T137/0324—With control of flow by a condition or characteristic of a fluid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/12—Condition responsive control

Abstract

Systems and methods for analysis of samples, and in certain embodiments, microfluidic sample analyzers configured to receive a cassette containing a sample therein to perform an analysis of the sample are described. The microfluidic sample analyzers may be used to control fluid flow, mixing, and sample analysis in a variety of microfluidic systems such as microfluidic point-of-care diagnostic platforms. Advantageously, the microfluidic sample analyzers may be, in some embodiments, inexpensive, reduced in size compared to conventional bench top systems, and simple to use. Cassettes that can operate with the sample analyzers are also described.

Description

The system and the device that are used for sample analysis
Technical field
The application relates in general to system, the apparatus and method for sample analysis, and in certain embodiments, relates to microfluid sample analysis device, microfluid sample analysis device be configured to hold wherein have sample box (cassette) with analyzing samples.Be provided in addition the box of sample analysis.
Background technology
The manipulation of fluid plays an important role in such as chemistry, microbiology and biochemical field.These fluids can comprise liquid or gas, and can provide reagent, solvent, reactant or purificant to chemistry or biological processes.---mixing of for example sample introducing, the introducing of reagent, the storage of reagent, the control of Fluid Flow in A, the separation of fluid, a plurality of fluids, the collection of refuse, for extraction and/or the transmission of fluid from a chip to next chip of the convection cell of sheet outer analysis---can increase the level of cost and complexity although various microfluidic methods and box (for example microfluid chemical examination) can provide cheap, sensitive and analysis platform accurately is fluid actuated.Usually, the microfluid box needs outside platform (for example analyzer) to carry out some like this and other fluid actuated.Exist various types of analyzers to process and analyze the microfluid sample, still, some such analyzers are expensive, heavy, be difficult to and/or the assembly of needs complexity handle fluid.Therefore, can the reduce cost, minification, simplification in this area uses, reduces the complexity of fluid actuated required component and/or the fluid actuated improvement that improves in the microfluid system will be favourable.
Summary of the invention
The system and method that is used for sample analysis has been described.In some cases, theme of the present invention relate to the product of associated, to the substituting solution of particular problem and/or a plurality of different purposes of one or more system and/or goods.
In one group of embodiment, provide serial of methods.In one embodiment, the method of analyzing the microfluid sample may further comprise the steps: the microfluid sample analysis that comprises shell device is provided, opening is arranged in the shell, wherein include box in the opening in shell, wherein the assembly of box or box comprises the passage that at least one wherein has fluid sample.The method comprises by being arranged on identification reader identification in the shell about the information of box, and processes the information that is input to the user interface in the described shell that is arranged on described sample analysis device.The method also relates to by the control pressurer system that is arranged in the shell exerts pressure at least one passage in the box, passes through at least one passage with mobile sample.The method comprises the startup optical system, this optical system makes from first measured zone of the light that is arranged on the first light source in the shell by box, and by being arranged on the first detector described optical system, relative with the first light source in the shell, detect the output optical transmission by the first measured zone of box.The method relates to by being arranged on the control system in the shell, the sample in the analysis box, and this control system is communicated by letter with identification reader, user interface, control pressurer system, optical system and humidity control system.The method can optionally comprise by the heating of the humidity control system in the shell that is arranged on sample analysis device box.
In another group embodiment, provide a series of microfluid sample analysis devices.In one embodiment, microfluid sample analysis device comprises: shell; Opening, be arranged in described shell and be configured to hold box, box has at least one passage that fluid sample is wherein arranged, its housing comprise be configured to described box on the matable assembly interface, detecting the assembly of the described box in the described shell, and the identification reader that arranges in the enclosure, is configured to read the information that is associated with box.Microfluid sample analysis device comprises in addition: user interface is arranged in the shell and is configured to make the user with input information sample analysis device; And be arranged on control pressurer system in the shell, at least one passage that this control pressurer system is configured in the box is exerted pressure, with mobile sample by at least one passage.Microfluid sample analysis device further comprises setting optical system in the enclosure, optical system comprises the first light source and the first detector that separates with the first light source at least, wherein the first light source is configured to make light pass through the first measured zone of box when inserting the sample analysis device, and wherein the first detector be set to relative with the first light source, to detect the output optical transmission by the first measured zone of box.Microfluid sample analysis device comprises in addition: humidity control system in the enclosure is set, and humidity control system comprises the heater that is configured to heat box; And control system, be arranged in the shell and be configured to and communicate by letter with identifying reader, user interface, control pressurer system, optical system and humidity control system, with the sample in the analysis box.
In another embodiment, microfluid sample analysis device comprises: shell; Opening, be arranged in described shell and be configured to hold box, described box has at least one passage that fluid sample is wherein arranged and at least one microfluidic channel and has cross sectional dimensions less than 1mm, wherein, described shell comprise be configured to described box on the matable assembly interface, to detect the assembly of the described box in the described shell.Microfluid sample analysis device comprises: be arranged on the control pressurer system in the shell, at least one passage that control pressurer system is configured in the box is exerted pressure, with mobile sample by at least one passage; And be arranged on optical system in the shell, optical system comprise a plurality of light sources and with the separated a plurality of detectors of a plurality of light sources, wherein light source is configured to make light pass through box when box inserts the sample analysis device, and wherein detector is set to relative to light source to detect the light quantity by box.A plurality of light sources comprise the first light source and the secondary light source adjacent with the first light source at least, wherein the first light source is configured to make light to pass through the first measured zone of box, and secondary light source is configured to transmit light by second measured zone adjacent with the first measured zone of box.In certain embodiments, unless light source is configured to close the first light source, otherwise do not start secondary light source.
In one group of embodiment, provide a kind of equipment.This equipment comprises the first assembly, and it comprises the first passage that forms with the first material, first passage comprise entrance, outlet and the entrance of first passage with export between have at least one part greater than 200 microns cross sectional dimensions.This equipment comprises the second assembly in addition, comprises the second channel that forms with the second material, second channel comprise entrance, outlet and the entrance of second channel with export between have at least one part less than 200 microns cross sectional dimensions.In certain embodiments, the first material is different from the second material (although in other embodiments, the first material can be identical with the second material).In certain embodiments, the water vapor permeable rate of the first material is lower than about 0.05gmm/m 2D.In certain embodiments, between the optical wavelength of 400nm and 800nm the optical transmittance of the second material greater than 90%.In addition, this equipment comprises fluid connector, is used for connecting first passage and second channel by the fluid mode, and fluid connector comprises fluid path, and fluid path comprises fluid path entrance and fluid path outlet.The fluid path entrance can connect by the fluid mode outlet of first passage, and the fluid path outlet can connect by the fluid mode entrance of second channel.This equipment is packaged as so that fluid connector does not connect first passage and second channel by the fluid mode.
In another group embodiment, provide a kind of device.This device comprises the first assembly, and the first assembly comprises the first passage that forms and comprise at least one entrance and an outlet with the first material, and first passage comprises at least one part that has greater than 200 microns cross sectional dimensions.This device comprises the second assembly in addition, and the second assembly comprises the second channel that forms and comprise at least one entrance and an outlet with the second material, and second channel comprises at least one part that has less than 200 microns cross sectional dimensions.In certain embodiments, the first material is different from the second material (although in other embodiments, the first material can be identical with the second material).In certain embodiments, the water vapor permeable rate of the first material is lower than about 0.05gmm/m 2D.In certain embodiments, between the optical wavelength of 400nm and 800nm the optical transmittance of the second material greater than 90%.This device comprises fluid connector in addition, can be connected to the first assembly and the second assembly, fluid connector comprises fluid path, fluid path comprises fluid path entrance and fluid path outlet, wherein when connecting, the fluid path entrance connects the outlet of first passage by the fluid mode, and the fluid path outlet connects the entrance of second channel by the fluid mode, is communicated with fluid between the second channel to allow first passage.Before using first, first passage does not have fluid to be communicated with second channel mutually, when using first, so that first passage is communicated with the mutual fluid of second channel.
When considered in conjunction with the accompanying drawings, according to the following detailed description of various non-limiting examples of the present invention, other advantages of the present invention and novel features will become obvious.
Description of drawings
Accompanying drawing is not to draw in proportion.In the accompanying drawings, usually represent the assembly that each shown in each view is identical or almost identical with identical Reference numeral.For the sake of clarity, in each accompanying drawing, do not mark each assembly.
Each embodiment is described with reference to the accompanying drawings by way of example, wherein:
Figure 1A illustrates according to the microfluid system of an embodiment and the block diagram of various assemblies, and various assemblies can be the parts of sample analysis device;
Figure 1B is according to the sample analysis device of an embodiment and the stereogram of box;
Fig. 2 is the stereogram according to the intraware of the sample analysis device of an embodiment in the removed situation of shell;
Fig. 3 is according to the box of an embodiment and the stereogram of fluid connector;
Fig. 4 illustrates fluid connector to be inserted stereogram in the box according to an embodiment;
Fig. 5 is the decomposition assembling figure according to the fluid connector of an embodiment;
Fig. 6 is the stereogram according to the box of an embodiment;
Fig. 7 is the decomposition assembling figure according to the box of an embodiment;
Fig. 8 is according to the box of an embodiment and the schematic diagram of fluid connector;
Fig. 9 A is the schematic diagram according to the box of an embodiment;
Fig. 9 B-9F is the schematic diagram according to the box that is formed by a plurality of assemblies of one group of embodiment;
Figure 10 is the part assembly drawing according to the sample analysis device of an embodiment;
Figure 11 is the top view according to the part assembling of the sample analysis device of an embodiment;
Figure 12 is another top view according to the part assembling of the sample analysis device of an embodiment;
Figure 13 is the schematic diagram according to the part of the sample analysis device of an embodiment;
Figure 14 is the schematic side elevation according to the part of the sample analysis device of an embodiment;
Figure 15 is the stereogram according to the vacuum system of the sample analysis device of an embodiment;
Figure 16 is the block diagram that the control system of the sample analysis device that the different assemblies from each according to an embodiment are associated is shown;
Figure 17-the 21st is according to the schematic diagram of the user interface of the sample analysis device of an embodiment;
Figure 22 is the schematic diagram that illustrates according to the microfluid system of the box of an embodiment; And
Figure 23 is the drawing as the measurement result of the optical density of the function of time that illustrates according to an embodiment.
The specific embodiment
Described the system and method that is used for sample analysis at this, and in certain embodiments, described microfluid sample analysis device, this microfluid sample analysis device is configured to hold the box that wherein comprises sample, to carry out sample analysis.
The applicant recognizes the needs to unique microfluid sample analysis device, and this microfluid sample analysis device is configured to process sample, to measure the level of one or more analytes (for example prostate specific antigen (PSA)) in the sample.As described below, the level of PSA level or other analytes can help to process prostate cancer or other diseases and/or health in the measurement blood sample.
Also can and be used for processing sample for other reasons with microfluid sample analysis device configuration described here, because the invention is not restricted to application-specific.For example, in one embodiment, microfluid sample analysis device configuration discussed here can be used for various types of protein analyses and/or DNA and/or RNA and analyze.In some cases, for example especially system and method described here can be used for being controlled at as microfluid immediately guard diagnostic platform, micro-fluid experiment chamber chemical analysis system, cell is cultivated or the fluid control systems of biochemical reactor various microfluid systems in Fluid Flow in A and mixing.In one embodiment, microfluid sample analysis device is arranged to various types of hematologies and/or urology applications.Microfluid sample analysis device configuration described here can be used for a variety of diagnosis and common chemistry and/or biological analysis.According to above with various application discussed here, the special configuration of sample analysis device can be used for application-specific and/or configuration is used for analyzing samples.
Following described in more detail, microfluid sample analysis device can be configured to hold and comprise that at least one wherein comprises the box of the passage of sample.The disposable assembly that the sample box can be configured to namely abandon after analyzing samples.
One group of example system and method are described below.
Figure 1A illustrates according to the microfluid system that FEEDBACK CONTROL can be provided of one group of embodiment and square frame Figure 10 of various assemblies.Microfluid system for example can comprise the box 20 that is associated in operation with one or more assemblies, one or more assemblies for example are for example to be used for that one or more fluids are introduced boxes and/or to be used for the speed of control Fluid Flow in A such as the Fluid Flow in A source 40(of pump), valve system 28(for example is used for starting one or more valves), detection system 34(is for example for detection of one or more fluids and/or processing) and/or humidity control system 41(is for example, be used for the heating of one or more zones and/or cooling with box), alternatively, Fluid Flow in A source 40 for example is to be configured to apply normal pressure or vacuum any one pump or vacuum plant among both (for example being used for one or more fluids are moved in the box/remove one or more fluids and/or be used for the speed of control Fluid Flow in A from box).Assembly can be at microfluidic device outside or inner, and can optionally comprise one or more processors, be used for the system of Control Component or assembly.In certain embodiments, one or more such assemblies and/or processor are associated with sample analysis device 47, this sample analysis device 47 be configured to process and/or analysis box in the sample that comprises.
Usually, as used herein, " in operation " and the assembly that one or more other assemblies are associated are indicated these assemblies to contact with mutual direct entity and are not needed to interconnect or the mode that is attached to each other directly interconnects, perhaps not directly to interconnect or be in contact with one another, but mechanically, electrical way (comprising via the electromagnetic signal by space transmission) or fluid mode interconnect (for example via such as the such passage of pipeline), thereby cause or so that the assembly that is associated like this can carry out the function that they are wanted.
The assembly that schematically shows in Figure 1A and other optional components (for example assembly described here) can be associated with control system 50 in operation.In certain embodiments, by using the feedback from the one or more events that occur in the microfluid system, control system can be used for the control fluid and/or carry out quality control.For example, control system can be configured to receive the input signal from one or more assemblies, calculate and/or control various parameters, the pattern of one or more signals or signal and the signal that is programmed in the control system are in advance compared, and/or send signal to one or more assemblies, regulate the operation of Fluid Flow in A and/or control microfluid system.Control system also can optionally be associated with other assemblies, and other assemblies for example are for example USB of user interface 54, recognition system 56, external communications units 58() and/or other assemblies, following described in more detail.
Box (for example microfluidic device) 20 can have be used to any suitable passage of expecting to analyze and/or the configuration of assembly.In one group of embodiment, box 20 comprises the reagent of storage, and it can be used for carrying out chemistry and/or biologically (for example immunity chemical examination), for example as described in more detail here.Box for example can comprise selective reagent entrance 62, and it is communicated with selective reagent storage area 64 fluids.Storage area for example can comprise one or more passages and/or reservoir, in certain embodiments, can use the fluid (liquids and gases that for example optionally separate by immiscible fluid, comprise immiscible reagent (for example reagent solution and washing lotion), following described in more detail) passage and/or reservoir are filled partially or entirely.Box also can comprise optional sample or reagent loading area 66, for example can be used for reagent storage zone 64 is connected to the fluid connector of optional measured zone 68.The measured zone that can comprise the one or more zones (for example measured zone) for detection of the composition in the sample can be communicated with and be couple to outlet 72 with optional refuse zone 70 fluids.In some cases, can or wherein form these and other device features on the different assemblies of box or layer, as described in more detail here.Therefore, should be appreciated that box can comprise single component or attached a plurality of assemblies in use, for example the combination of goods with attached fluid connector described here.In one group of embodiment, fluid can flow in the direction of arrow shown in the drawings.Further describing and example of these and other assemblies is provided in more detail below.
In certain embodiments, before sample was introduced box, the part 71 and 77 of box did not have fluid to be communicated with mutually.In some cases, before the first use of box, part 71 and 77 does not have fluid to be communicated with mutually, wherein when using first, the mutual fluid of these parts is communicated with.Before using first and/or before sample is introduced box, part 71 and 77 is mutually fluid connection but in other embodiments.Other configurations of box also can.
Shown in the exemplary embodiment shown in Figure 1A, one or more Fluid Flow in As source 40(is pump and/or vacuum plant or other control pressurer systems for example), valve system 28, detection system 34, humidity control system 41 and/or other assemblies in operation can with other zones of reagent entrance 62, reagent storage zone 64, sample or reagent loading area 66, conversion zone 68, refuse zone 70, outlet 72 and/or box 20 in one or more being associated.The detection of processing or event can produce the pattern of signal or signal in one or more zones of box, and the pattern of signal or signal can be transferred to control system 50.Signal (a plurality of signal) based on the control system reception, one or more by control pump, vacuum plant, valve system, detection system, humidity control system and/or other assemblies for example can feedback be used for handling the fluid between each zone in fluid in each zone in these zones of microfluidic device and/or these zones.
Forward Figure 1B to Fig. 2 to, an embodiment of microfluid sample analysis device 100 is shown.Shown in the exemplary embodiment of Figure 1B, analyzer 100 comprises shell 101, shell 101 be configured to cover or keep below the assembly of analyzer 100 in greater detail.Opening 120 in the shell 101 is configured to hold box 20.Following described in more detail, analyzer 100 can also comprise the user interface 200 that is arranged in the shell 101, and user interface 200 is arranged to by the user input information sample analysis device.In this particular example, user interface 200 comprises touch-screen, but as described below, also can be therewith configuration user interface differently.
Fig. 2 illustrates the sample analysis device 100 shown in Figure 1B, except shell 101 and user interface 200 parts are got rid of, to describe some other assemblies that can be arranged in the shell 101.The below will describe these assemblies in more detail, and these assemblies include but not limited to be configured to the vacuum system for example to Fluid Flow in A source 40(that box 20 is exerted pressure), be configured to read the identification reader 60 of the information that is associated with box and comprise be configured to and cartridge interface with the mechanical subsystem 79 of the assembly that detects the box in the shell.As mentioned above, the opening in the shell 120 is configured to hold box 20.As shown in Figure 2, in one embodiment, opening 120 is configured to elongated groove.Can dispose in this way opening 120, to hold basically card-like box.Should be appreciated that in other embodiments, can form and dispose opening 120 by different modes, because the invention is not restricted to this.
As mentioned above, microfluid sample analysis device 100 for example can be configured to hold various types of box 20(, microfluidic device).Fig. 3 to Fig. 9 illustrates the various exemplary embodiments of the box 20 that uses with analyzer 100.Such as Fig. 3 to Fig. 4 and shown in Figure 6, box 20 can be basically card-like (that is, being similar to card key) with basically strict plank frame.
Box 20 can be configured to comprise fluid connector 220, shown in the exemplary embodiment as shown in Figure 4, fluid connector 220 can buckle into an end of box 20.In certain embodiments, fluid connector can be used for one or more fluids (for example, sample or reagent) are introduced box.
In one group of embodiment, fluid connector is used for connecting two (or a plurality of) passages of box in first use procedure by the fluid mode, and these passages do not connect before using first.For example, box can be included in two passages that do not have fluid to be communicated with before the using first of box.Disconnected passage may be favourable in some cases, for example is used for different reagent storage at each passage.For example, first passage can be used for storing dried reagent, and second channel can be used for storing wet reagent.Make passage be separated from each other the long-time stability that can improve the reagent of storing in each passage at entity, for example the reagent by the storage of protection dry type makes it not be subjected to the issuable influence of moisture of reagent of wet type storage.When using first, can via the fluid connector interface channel, be communicated with the fluid between the passage that allows box.For example, the fluid of connection can be worn out the entrance of covering box and/or the sealing of outlet, inserts in the box to allow fluid connector.
As used herein, use first the box time before by prospective users after " before the first use of box " is illustrated in commercial distribution.Use first any step that can comprise requirement user manipulation device.For example, use first to relate to and for example wear out sealed entry reagent is introduced box, connect two or more passages so that the fluid between the passage is communicated with, the preparation of before sample analysis, installing (for example, with the reagent charging apparatus), with the sample charging apparatus, in the zone of device, prepare sample, carry out with the reaction of sample, detect sample etc. one or more steps.Under this background, use first not comprise manufacturing or other preparation or quality control step of being taked by the manufacturer of box.Those skilled in the art know the implication of using first under this background, and can determine easily whether box of the present invention has experienced first use.In one group of embodiment, box of the present invention (for example, after finishing chemical examination) after using first can be abandoned, and this is obvious especially when using these devices first, because after using first, use this device (for example, being used for carrying out the second chemical examination) usually infeasible.
Can use various mechanisms that box is connected to fluid connector.For example, fluid connector can comprise at least one the nonfluid parts with the parts complementation of box, thereby is connected with nonfluid between the box by attached formation fluid connector.The nonfluid complementary part for example can be the projecting member of fluid connector and the corresponding complementary chamber of box, and it can help the user that fluid connector is aimed at box.In some cases, when alignment member containing fluid assembly (for example, when inserting fluid assembly in the alignment member) and/or in the expection use procedure of device, this parts convection cell connector is with respect to the mobile actual resistance that produces of box and/or alignment member.Fluid connector and/or box can optionally comprise one or more parts, for example buckle into parts (for example, breach), groove, the opening that is used for inserting clip, zipper strip mechanism (zip-tie mechanism), pressure fittings, frictional force accessory, screw thread coupling (for example the screw accessory, buckle into accessory, bonding accessory, magnetic connector or other suitable coupled connection mechanisms.Fluid connector and liquid-tight formula and/or the hermetically sealing that can relate to being connected of box between the formation assembly.The attached of fluid connector and box can be reversible or irreversible.
As shown in the figure, box 20 can be configured to comprise fluid connector 220.Especially, box 20 can comprise the fluid connector alignment member 202 that is configured to hold connector 220 and is mated.For example, alignment member can be extended from the bottom of box, and comprises chamber, and it is configured and is arranged as and holds and mesh fluid connector, thereby with respect to the bottom of box fluid connector is arranged in the configuration that sets in advance.Shown in the illustrative examples of Fig. 4, box can comprise the alignment member of extending approximately perpendicular to box.In other embodiments, alignment member can be similar to and be parallel to the box extension.
In certain embodiments, the configuration adjustment of alignment member and fluid connector can be inserted alignment member by sliding action with fluid connector for allowing.For example, when fluid connector is inserted alignment member, can make fluid connector with respect to one or more surface slidings of alignment member.
Shown in the exemplary embodiment as shown in Figure 5, fluid connector 220 can comprise the basically passage 222 of U-shaped, and passage 222 can be preserved fluid and/or reagent (for example, fluid sample) before being connected to box.Passage 222 can be installed between two shell components that form connector 220.In certain embodiments, before fluid connector was connected to box, fluid connector can be used for collecting sample from patient.For example, can obtain thorn with pocket knife or other suitable instruments and refer to blood sample, then collect blood samples by fluid connector 220 and by the capillarity passage 222 of packing into.In other embodiments, fluid connector 220 can be configured to wear out patient's finger and with sample collection in passage 222.In certain embodiments, fluid connector did not comprise sample (perhaps reagent) before being connected to box, but allowed simply the fluid between two or more passages of box to be communicated with when connecting.In one embodiment, form the U-shaped passage by capillary.Fluid connector also can comprise the configuration of other passages, and in certain embodiments, and fluid connector can comprise by the fluid mode and interconnecting or mutually discrete passage more than.
Fig. 6 to Fig. 9 illustrates in greater detail the various exemplary embodiments of box 20.Decomposition assembling figure such as Fig. 7 is schematically shown, and box 20 can comprise box body 204, and box body 204 comprises at least one passage 206, and it is configured to hold sample or reagent, and sample or reagent can flow through passage 206.Box body 204 also can comprise setting latch 208 at one end, and itself and 202 interlockings of fluid connector alignment member are used for buckling into assembling.
Box 20 can also comprise upper and lower cover plates 210 and 212, and it for example can be made by transparent material.In certain embodiments, cover plate can be the form of the adhesive of biocompatible, and for example can be made by condensate (for example, polyethylene (PE), cyclic olefine copolymer (COC), polyvinyl chloride (PVC)) or inorganic material.In some cases, one or more cover plates are forms (for example, band) of binder film.Use for some, with the material of cover plate be sized to so that cover plate can not permeate steam basically.In other embodiments, cover plate can without bonding force, still can pass through directly to use heat, laser energy or ultrasonic energy and microfluid substrate thermal bonding.Can be with one or more cover plates with any entrance of the passage of box and/or exit seal (for example by placing adhesive at entrance and/or outlet).In some cases, cover plate seals the reagent of the one or more storages in the box basically.
As shown in the figure, box body 204 can comprise one or more ports 214 of the passage 206 that is couple in the box body 204.These ports 214 can be configured to when fluid connector 220 be couple to box 20 with the passage 206 in the box body 204 when being fluidically connected to the passage 222 in the fluid connector 220, aim in the fluid connector 220 the basically passage 222 of U-shaped.In certain embodiments, also can be with the passage 222 of U-shaped basically by being fluidically connected to passage 207, thus couple passage 206 and 207.As shown in the figure, cover plate 216 can be arranged on port 214 tops, and (for example, by connector 220 or by other devices) can be configured to burst or opening with cover plate 216, to connect two passages 206 and 222 by the fluid mode.Additionally, cover plate 218 can be set to cover in the box body 204 port 219(for example, vacuum ports).Following described in more detail, port 219 can be configured to by the fluid mode Fluid Flow in A source 40 is connected with passage 206, pass through box with mobile sample.Cover plate 218 on the port 219 can be configured to burst or opening, by the fluid mode passage 206 is connected with Fluid Flow in A source 40.
Box body 204 can optionally comprise liquid containing zone (liquid containment region), and for example the refuse zone comprises for example refuse dish of absorbent material 217().In certain embodiments, the liquid containing zone comprises the zone of catching the one or more fluids that flow in the box, allows simultaneously gas or other fluids in the box to pass through this zone.In certain embodiments, can realize this point for liquid-absorbing by one or more absorbent materials are set in the liquid containing zone.This configuration can be used for separating with water seeking liquid from flow eliminating bubble and/or with hydrophobic liquid.In certain embodiments, the liquid containing zone prevents that liquid from passing through this zone.In some such situations, by basically catching all liq in the box, the refuse zone can be served as in the liquid containing zone, thereby prevents that liquid from flowing out box (for example, when allowing gas to overflow (escape) from the outlet of box).For example, the refuse zone is used in during the sample analysis, at sample and/or reagent by after the passage 206, with sample and/or reagent storage in box.When box was used as diagnostic tool, these and other layouts came in handy, and were exposed under harmful fluid potential in the box because the liquid containing zone can prevent the user.
The schematic diagram of box 20 shown in Figure 8 illustrates an embodiment, and wherein box 20 comprises first passage 206 and the second channel 207 that separates with first passage 206.In one embodiment, passage 206,207 cross-sectional dimension scope be from about 50 microns to about 500 microns, but followingly described in more detailly can use other channel sizes and configuration.
First passage 206 can comprise the one or more measured zone 209 for analyzing samples.For example, in an illustrative examples, passage 206 is included in for example serial or parallel connection of four measuring zone 209(of using during the sample analysis).
In certain embodiments, one or more measured zone are forms (zone that for example, relates to bending channel) of bending area.For example can be by being at least 0.25mm 2, 0.5mm at least 2, 0.75mm at least 2Perhaps 1.0mm at least 2Area limit bending area, wherein at least 25% of the area of bending area, 50% or 75% comprises optical detection path.The detector that can allow to carry out the measurement of individual signals by the adjacent segment more than of bending area is set to bending area adjacent.In some cases, passage 206 is by being fluidically connected at least bending area of dual serial connection.
As described here, first passage 206 and/or second channel 207 be used in box use first before storage for the treatment of with one or more reagent of analyzing samples.In certain embodiments, do reagent storage in passage or part of box, wet reagent storage is in another passage or part of box.Perhaps, two of box separating parts or passage can hold dried reagent and/or wet reagent.Reagent for example can be used as liquid, gas, gelinite, a plurality of particle or film storage and/or processes.Reagent can be arranged on any appropriate location of box, include but not limited in the passage, in the reservoir, on the surface, in the barrier film or on the barrier film, alternatively, barrier film can be the part in reagent storage zone.Reagent can be associated with box (the perhaps assembly of box) in any suitable manner.For example, reagent can be crosslinked (for example, covalently or ion ground), absorb or absorb on (Physical Absorption) surface in box.In a particular embodiment, apply passage all or part of (for example passage of the fluid path of fluid connector or box) with anti-coagulants (for example heparin).In some cases, liquid is included in the passage or reservoir of box before before using first and/or with sample, introducing box.
In certain embodiments, the reagent of storage can comprise the fluid column (fluid plug) that arranges according to linear precedence, therefore during use, when the direction of flow reflecting point, transmits them according to predefined procedure.The box that is designed to chemically examine for example can comprise antibody fluid, the purificant fluid of purificant fluid, mark and amplify fluid that all storage wherein continuously.When storing fluid, can pass through immiscible in fact separation of the fluid (for example, such as the such gas of air) they are kept separating, therefore the fluid reagent that usually can react to each other when contacting can be stored in the public passage.
Reagent storage can be continued various time quantums in box.For example, reagent storage can be surpassed 1 hour, surpass 6 hours, surpass 12 hours, surpass 1 day, surpassed for 1 week, surpass 1 month, surpass 3 months, surpass 6 months, surpass 1 year or above 2 years.Optionally, in order to prolong memory time, can process by rights box.For example, the regent pack of storage can be contained in wherein box vacuum seal, be stored in the dark surrounds and/or storage (for example, is lower than zero degrees celsius) at low temperatures.The time length of storage depends on one or more following factors, the form of the particular agent of for example using, the reagent of storage (for example, wet or do), be used to form at the bottom of substrate and tectal size and material, the adhesive lining with tectal method and how process as a whole or the storage box.The storage of reagent in the passage (for example, fluid or dried reagent) can relate to the entrance and exit of seal channel before using first or during the packing of device.
Shown in the exemplary embodiment shown in Fig. 8 and Fig. 9 A-9F, before fluid connector 220 is connected to box 20, passage 206 and passage 207 each other not fluid be communicated with.In other words, in certain embodiments, before introducing box before the first use and/or with sample, two each other not fluid connections of passage.Especially, as shown in the figure, the passage 222 of the basically U-shaped of connector 220 can connect first passage 206 and second channel 207 by the fluid mode, so the reagent in the second channel 207 can pass through U-shaped passage 22, and optionally moves to the measured zone 209 in the first passage 206.In other embodiments, two passages 206 and 207 are introduced box before using first and/or with sample before mutually fluid be communicated with, but fluid connector further connects two passages (for example, forming closed-loop system) when using first.
In certain embodiments, box described here can comprise one or more microfluidic channel, but such box is not limited to microfluid system, and can be relevant with the fluid system of other types.As used herein, " microfluid " refers to box, device, equipment or the system that comprises at least one fluid passage, and the cross-sectional dimension of fluid passage is less than 1mm, and the ratio of length and cross-sectional dimension is 3:1 at least.As used herein, " microfluidic channel " is to satisfy the passage of these standards.
" cross sectional dimensions " of passage (for example diameter) is with perpendicular to the orientation measurement of Fluid Flow in A.The cross-sectional dimension of most of fluid passages is less than 2mm, in some cases less than 1mm in the assembly of box described here.In one group of embodiment, whole fluid passages of box all are that microfluid or cross-sectional dimension are not more than 2mm or 1mm.Another the group embodiment in, the cross-sectional dimension of passage less than 500 microns, less than 200 microns, less than 100 microns, less than 50 microns or less than 25 microns.In some cases, can being sized to so that fluid can freely flow through goods or substrate passage.For example also can be with certain volume or the linear flow rate that allows fluid in the passage that be sized to of passage.Certainly, can change the quantity of passage and the shape of passage by well known to a person skilled in the art any proper method.In some cases, can use passage or capillary more than one.
Passage can be included in the upper or parts that guide at least in part Fluid Flow in A wherein of goods (for example box).Passage can have any suitable shape of cross section (circle, ellipse, triangle, irregularly shaped, square or rectangle etc.), and can be capped or not cover.In the embodiment that passage is covered fully, at least one part of passage can have complete besieged cross section, and perhaps the whole passage except its entrance and exit is surrounded fully along its whole length.Passage also can have the aspect ratio of the 2:1 at least ratio of average cross-section size (length with), more typically is at least 3:1,5:1 or 10:1 or larger.
Box described here can comprise passage or the passage fragment that is arranged on the box one or both sides.In some cases, passage is formed on the surface of box.Can be by the interference passage interface channel fragment of passing box.In certain embodiments, the passage fragment was used for before the terminal use uses first reagent storage at device.Even during in (for example between the time of shipment at box) during the routine processing of box and in box experience physical shock or vibration, the position of passage fragment also can allow fluid reagent to store the longer time cycle in the situation that does not need to mix in the geometry in particular of passage fragment and the box.
In certain embodiments, box is included in the optical element that the side relative with one group of fluid passage of box made." optical element " is for the parts that are illustrated on goods or the box or wherein form or arrange, it is provided for inciding the light on goods or the box when not having element and the direction (for example, via refraction or reflection), focus, polarity and/or other character that change incidence electromagnetic radiation.For example, optical element can comprise lens (for example, recessed or protruding), mirror, grating, groove or in box or the box miscellaneous part that forms or arrange.But itself there is not the box of unique components not consist of optical element, even one or more characteristics of incident light can change when interacting with box.Optical element can guide incident light to pass through box, so that most of light is from specific region (for example, the interference portion between the fluid passage) scattering of box.By reducing the light quantity of incident on these interference portions, when using some Systems for optical inspection, can reduce the noisiness in the detection signal.In certain embodiments, optical element is included on the surface of box or the vee gutter that wherein forms.Can select the depanning angle of vee gutter, so that change at a certain angle direction perpendicular to the incident light on box surface according to refraction coefficient and the cassette material of external agency (for example air).In certain embodiments, one or more optical elements are arranged between the adjacent segment of bending area of measured zone.
The part of box or box can be by any material manufacturing that is suitable for forming passage or other assemblies.The non-limiting example of material comprises condensate (for example polyethylene, polystyrene, polymethyl methacrylate, Merlon, poly-(dimethyl siloxane), PVC, PTFE, PET and cyclic olefin copolymer), glass, quartz and silicon.The material that forms box and any associated component (for example, cover plate) can be hard or pliable and tough.For example according to the hardness of material, material for will by it fluid inertia (for example not being degraded), material in the durability of the temperature of using specific device, material to the transparency/opacity of light (for example, in ultraviolet ray and visible region) and/or for the method with this material manufacture component, those skilled in the art can easily select suitable material.For example; for injection molding or other extruded products; the material that uses (for example can comprise thermoplastic; polypropylene, Merlon, acrylonitrile-butadiene-styrene copolymer, nylon 6), elastomer (for example; polyisoprene, isobutylene-isoprene, nitrile, neoprene, ethylene-propylene, chlorosulfonated polyethylene, silicones), thermosetting resin (for example, epoxy resin, unsaturated polyester resin, phenolic resins) or their combination.Following described in more detail, can be for example based on above with those factors described here, form the box that comprises two or more assemblies or layer with different materials, so that assembly is fit to the major function (a plurality of function) of each assembly.
In certain embodiments, material and the size (for example thickness) with box and/or cover plate is chosen as so that it can not permeate steam basically.For example, be designed to before using first, one or more fluid storage box wherein can comprised cover plate that cover plate comprises the known material that high vapor barrier performance is provided, for example metal forming, some condensate, some pottery and their combination.The below provides the example of the material with low vapour permeability.In other cases, come selection material based on the shape of box and/or configuration at least in part.For example, some material can be used for forming plane device, and other materials is more suitable in forming crooked or erose device.
In some instances, box comprises the combination of two or more materials, for example goes up above-mentioned listed material.For example, the passage (for example, passing through injection molding) of box can be formed with polystyrene or other condensates, and the belt of biocompatible seal channel can be used for.The belt of biocompatible or flexible material can comprise improve vapor barrier character well known materials (for example, metal forming, condensate or known other materials with high vapor barrier performance), and can optionally allow by wearing out or peel belt, the access entrance and exit.Can make in all sorts of ways sealing microfluidic channel or portion of channel, perhaps a plurality of layers of engagement device include but not limited to use adhesive, use cohesive belt, gummed, joint, lamination material, perhaps by mechanical means (for example, clamp, buckle into mechanism etc.).
In some instances, box comprises the combination of two or more separation assemblies (for example, layer or box) of installing together.On the different assemblies of box or wherein can comprise independently channel network (for example 71 parts of Figure 1A and 77 parts), channel network can optionally comprise first use before storage reagent wherein.For example by method described here, can the assembly that separate be installed together or interrelated by any suitable device, for example to form single (compound) box.In certain embodiments, two or more channel networks are arranged in the different assemblies or layer of box, and before using first, do not connect two or more channel networks by the fluid mode, connect two or more channel networks but when using first, pass through the fluid mode, for example by using fluid connector.In other embodiments, two or more channel networks connected by the fluid mode before using first.
Preferably, can adjust individually each different assembly or the layer that forms compound box according to the design function of assembly or layer.For example, in one group of embodiment, an assembly can adjusting compound box is used for the wet reagent of storage.In some such embodiment, can form this assembly with the material with low vapour permeability.Additionally or alternatively, for example, according to the Fluid Volume that will store, the storage area of box can be made to compare with the passage of other assemblies that are not used in fluid storage or zone and have larger cross sectional dimensions.The material that is used to form box can conform to the manufacturing technology that is suitable for forming larger cross sectional dimensions.Different with it, in certain embodiments, the second assembly that is adjusted for the detection of analyte can comprise the channel part with smaller cross-sectional area size.In certain embodiments, less cross sectional dimensions for example can be used for allowing the fluid volume for given, more time of contact between the fluid (for example, reagent solution or washing lotion) that flows in passage and the analyte that joins channel surface to.Additionally or alternatively, the channel part of the second assembly can have lower surface roughness (for example, to increase the signal to noise ratio between detection period) than the channel part of another assembly.In certain embodiments, the smaller cross-sectional area size of the channel part of the second assembly or lower surface roughness may need some and manufacturing technology or the different manufacturing technologies of fabrication tool or the fabrication tool of the different assemblies that are used to form box.In addition, in some specific embodiments, the notable feature that is used for the material of the second assembly is for protein adherence and detection.Therefore, preferably be formed for the different channel parts of different purposes at the different assemblies of box, then can before prospective users uses, be bonded together.The below provides other advantages and the feature of assembly and example.
Device shown in Fig. 9 B to Fig. 9 E can comprise a plurality of assembly 20B and the 20C that is combined to form single box.Shown in these illustrative examples, assembly 20B can comprise the first side 21A and the second side 21B.Assembly 20C can comprise the first side 22A and the second side 22B.In certain embodiments, can be on the first side place of assembly, the first side or in the first side, form device assembly described here or parts (for example, passage or other entities) on the second side place of assembly, the second side or in the second side and/or by assembly.For example, be schematically shown such as Fig. 9 C, assembly 20C can comprise the passage 206 with entrance and exit, and can form with the first material.Passage 206 can have as any suitable configuration described here, and can comprise for example one or more reagent storage zone, measured zone, liquid containing zone, Mixed Zone etc.In certain embodiments, passage 206 is not formed whole thickness by assembly 20B.That is to say, can in a side place of assembly or a side, form passage.Optionally, can use as another assembly of cover plate described here (for example, belt (not shown)), box or layer or other suitable assemblies and surround passage 206.In other embodiments, passage 206 is formed whole thickness by assembly 20B, and need cover plate to surround passage in the both sides of box.
Assembly 20B can comprise the passage 207 with entrance and exit, and can form with the second material, and the second material can be identical with the first material, also can be different.Passage 207 also can have as any suitable configuration described here, and can form the whole thickness by assembly 20C, also can not pass through the whole thickness of assembly 20C.Can passage 207 be surrounded with one or more cover plates.In some cases, cover plate is not the assembly that comprises one or more fluid passages (for example assembly 20C).For example, cover plate can be biocompatible belt or other surface that arranges between assembly 20B and the assembly 20C.In other embodiments, can passage 207 be surrounded basically by assembly 20C.That is to say that when assembly 20B and assembly 20C direct neighbor, the surperficial 22A of assembly 20C can form the part of passage 207.
Be schematically shown such as Fig. 9 D and Fig. 9 E, assembly 20B and assembly 20C can be smooth basically, and can a top that be placed on another.But the two or more assemblies that usually, form box can be about placing with any suitable configuration each other.In some cases, assembly is placed (for example, side by side, a top that is placed on another) adjacent to each other.The first assembly can be fully overlapping or be only had the part of assembly overlapping.For example, be schematically shown such as Fig. 9 D and Fig. 9 E, assembly 20C can extend beyond assembly 20B, so the part of assembly 20C is not overlapping by assembly 20B or covering.In some cases, this configuration is favourable, wherein assembly 20C be substantial transparent and need light by the part (for example, conversion zone, measured zone or surveyed area) of assembly, and wherein assembly 20B be opaque or not as assembly 20C transparent.
In addition, the first assembly and the second assembly can comprise any suitable shape and/or configuration.For example, in certain embodiments, the first assembly comprises the parts with the parts complementation of the second assembly, is connected thereby form nonfluid between the first assembly and the second assembly.Complementary part for example can help aiming at of assembly process the first assembly and the second assembly.The example of complementary part is described here.In some cases, coupled connection mechanism or matching mechanism (for example described here) can be used for coupling the first assembly and the second assembly.
In certain embodiments, the first assembly and the second assembly integrally can be interconnected.As used herein, when referring to two or more object, term " integrated connection " is illustrated in the normal use procedure object and can not becomes and be separated from each other, for example can not manual separation; Separate and to need at least tool using, and/or by damaging at least one assembly wherein, for example by destroying, peel off or separating the assembly that tightens together via adhesive or instrument.In normal use procedure, the assembly of integrated connection can irreversibly be attached to each other.For example, can be by using adhesive or passing through other joint methods with assembly 20B and assembly 20C integrated connection.In other embodiments, two or more assemblies of box reversibly can be attached to each other.
As described here, in certain embodiments, at least the first assembly that forms compound box can form with different materials with the second assembly.Can design system to so that the first assembly comprises the first material that helps or strengthen one or more functions of the first assembly.For example, if with the first component design be before user's first use (for example, at least one sky, a week, one month or 1 year) storage of liquids reagent (for example being stored in the passage of assembly), can select to have the first material of low vapour permeability, thereby reduce the liquid evaporation capacity in time of storage.But should be appreciated that in certain embodiments, identical material can be used for a plurality of assemblies (for example, layer) of box.For example, can form with the material with low water vapor permeability the first assembly and second assembly of box.
All or part of the material that is used to form the parts of device or assembly for example can have and is lower than about 5.0gmm/m 2D, be lower than about 4.0gmm/m 2D, be lower than about 3.0gmm/m 2D, be lower than about 2.0gmm/m 2D, be lower than about 1.0gmm/m 2D, be lower than about 0.5gmm/m 2D, be lower than about 0.3gmm/m 2D, be lower than about 0.1gmm/m 2D or be lower than about 0.05gmm/m 2The water vapor permeability of d.In some cases, water vapor permeability for example can be at about 0.01gmm/m 2D and about 2.0gmm/m 2Between the d, about 0.01gmm/m 2D and about 1.0gmm/m 2Between the d, about 0.01gmm/m 2D and about 0.4gmm/m 2Between the d, about 0.01gmm/m 2D and about 0.04gmm/m 2Between the d or about 0.01gmm/m 2D and about 0.1gmm/m 2Between the d.For example can measure water vapor permeability during at 40 ° of C in 90% relative humidity (RH).
In certain embodiments, the second assembly is not used in storage of liquids before the user uses, and can form with water vapor permeability second material higher than the first assembly.For example, the second material can have and is higher than about 0.05gmm/m 2D, be higher than about 0.1gmm/m 2D, be higher than about 0.3gmm/m 2D, be higher than about 0.5gmm/m 2D, be higher than about 1.0gmm/m 2D, be higher than about 2.0gmm/m 2D, be higher than about 3.0gmm/m 2D, be higher than about 4.0gmm/m 2D or be higher than about 5.0gmm/m 2The water vapor permeability of d.
In some cases, be used to form the water vapor permeability of the first material of the first assembly of box than low at least 1.5 times, at least 2 times, at least 3 times, at least 5 times, at least 10 times, at least 20 times, at least 50 times or at least 100 times of the water vapor permeability of the second material of the second assembly that forms box.
The water vapor permeability of material is known, perhaps can be determined by those skilled in the art.For example, usually have such as the such material of some cyclic olefine copolymer and be lower than about 0.1gmm/m 2The water vapor permeability of d is (for example, at 0.02 – 0.04gmm/m 2Between the d), and some polypropylene has about 0.5gmm/m 2D or higher water vapor permeability.Some PET has about 1.0gmm/m 2The vapour permeability of d, some PVC has about 1.2gmm/m 2The water vapor permeability of d, and some Merlon has about 4.0gmm/m 2The water vapor permeability of d.
In certain embodiments, can with so that be more suitable in the material of processing under certain condition form device one or more assemblies or the layer.For example, the fusion temperature that can be based in part on material is come selection material, adapts to allow it and for example some fabrication tool described herein and/or method (for example, being used to form the passage of some size).In certain embodiments, the material that is higher than about 80 ° of C, is higher than about 100 ° of C, is higher than about 130 ° of C, is higher than about 160 ° of C or is higher than about 200 ° of C with fusion temperature forms the first assembly.The material of in certain embodiments, being less than or equal to about 200 ° of C, being less than or equal to about 160 ° of C, being less than or equal to about 130 ° of C, being less than or equal to about 100 ° of C or being less than or equal to about 80 ° of C with fusion temperature forms the second assembly that is designed to the combination of the first assembly.Other fusion temperatures also are fine.
In one group of specific embodiment, the material that is higher than the fusion temperature of the material that is used to form assembly 20C with fusion temperature forms assembly 20B.In a particular embodiment, the material that is higher than the fusion temperature of the material that is used to form other assemblies of box with fusion temperature is formed for the assembly of liquid reagent storage.
In certain embodiments, the box that comprises the first assembly and the second assembly comprises the channel part with varying cross-section size in each different assembly.As described here, function and other factors that can be based in part on channel part are selected specific cross sectional dimensions, and wherein miscellaneous part or the assembly with respect to device arranges channel part.
The channel part of box can have any suitable cross sectional dimensions.For example, the first assembly can comprise first passage, first passage comprise at least one for example cross sectional dimensions greater than about 50 microns, greater than about 100 microns, greater than about 200 microns, greater than about 350 microns, greater than about 500 microns, greater than about 750 microns or greater than the about part of 1mm.In some cases, before the user uses first, the channel part with larger cross sectional dimensions can be used for the liquid that storage wherein comprises.
In some cases, the second assembly of box comprises second channel, and second channel comprises that at least one cross sectional dimensions is at least 1.5 times, at least 2 times, at least 3 times, at least 5 times, at least 7 times or at least 10 times part of the first passage cross sectional dimensions partly of box the first assembly.This species diversity of cross sectional dimensions can be because the second channel in the second assembly partly has different functions than the channel part of the first assembly.The second channel of the second assembly can comprise at least one cross sectional dimensions for example less than about 1mm, less than about 750 microns, less than about 500 microns, less than about 350 microns, less than about 200 microns, less than about 100 microns or less than about 50 microns part.For example, in some cases, have the passage of smaller cross-sectional area size than the first passage of the first assembly applicable to the surveyed area of device, be used for the speed of control Fluid Flow in A, perhaps be used for other purposes.
In certain embodiments, the channel part in the different assemblies of box has different cross sectional dimensions, and forms with the material with different fusion temperatures.For example, in some instances, can be with than low melting temperature (for example having, be lower than about 100 ° of C) material form and (for example to have the smaller cross-sectional area size, less than about 300 microns, less than about 200 microns or less than about 100 microns) channel part, and with (for example having higher melting temperature, be higher than about 100 ° of C) material form and to have larger cross sectional dimensions (for example, greater than about 100 microns, greater than about 200 microns or greater than about 300 microns) channel part.
In some cases, can have different surface roughnesses from the different assemblies of device or the passage of layer.For example, than obsolete passage in Check processing or the passage that uses in the Check processing that requires than muting sensitivity, the passage that is designed to a surveyed area part can have lower surface roughness.The lip-deep actual roughness of channel part may cause unwanted scattering or light with undesirable Angulation changes direction.To have different surface roughnesses may be favourable from the different assemblies of device or the passage of layer, because than the passage with high surfaces roughness, having may be more complicated and/or more expensive than the manufacturing of the passage of low surface roughness.For example, than the instrument of making by machining, (and therefore some fabrication tool that is used for moulding by micromachined or photoetching technique manufacturing has lower surface roughness, formation has the channel part than low surface roughness), but may make more complicated and/or more expensive.
In certain embodiments, at least a portion of the first passage of the first assembly can have and is less than or equal to about 10 microns root mean square (RMS) surface roughness.In certain embodiments, the rms surface roughness for example can be less than or equal to about 5 microns, is less than or equal to about 3 microns, is less than or equal to about 1 micron, is less than or equal to about 0.8 micron, is less than or equal to about 0.5 micron, is less than or equal to about 0.3 micron or be less than or equal to about 0.1 micron.The rms surface roughness is to well known to a person skilled in the art term, and can be expressed as:
&sigma; h = [ < ( z - z m ) 2 > ] 1 / 2 = [ 1 A &Integral; A ( z - z m ) 2 dA ] 1 / 2
Wherein, A is surface to be checked, and | z-z m| be that local height with respect to average departs from.
At least a portion of the second channel of the second assembly for example can have the root mean square surface roughness different from the first assembly.Second channel part for example can have greater than about 0.1 micron, greater than about 0.3 micron, greater than about 0.5 micron, greater than about 1 micron, greater than about 3 microns, greater than about 5 microns or greater than about 10 microns rms surface roughness.
In certain embodiments, the first assembly of box and the second assembly have optical clarity in various degree.For example, the first assembly can be basically opaque, and the second assembly can substantial transparent.The assembly of substantial transparent is applicable to the sample that comprises in the assembly or the optical detection of analyte.
In one group of embodiment, between light (for example, the light in the visible range) wavelength of 400nm and 800nm, be used to form the optical transmittance of material of assembly (for example, the first assembly or the second assembly) of box greater than 90%.Be for example about 2mm(or in other embodiments, approximately 1mm or approximately 0.1mm by thickness) material, can measure optical transmittance.In some instances, between the wavelength of light of 400nm and 800nm, optical transmittance is greater than 80%, greater than 85%, greater than 88%, greater than 92%, greater than 94% or greater than 96%.Another assembly of device can be used in optical transmittance between the wavelength of light of 400nm and 800nm less than 96%,, less than 94%, less than 92%, less than 90%, less than 85%, less than 80%, less than 50%, less than 30% or less than 10% material formation.
As described here, the different assemblies of device or layer can comprise the passage of making by the fabrication tool of different (perhaps identical) and/or method.For example, can use injection molding to form an assembly, use different technology (for example, machining) to form another assembly.In another example, can form by moulding (for example, injection molding) technique the first passage part of the first assembly, moulding process relates to the use by the fabrication tool that grinds or make by photoetching process.In some cases, can have basically circular transverse cross-sectional area by grinding the formed channel part of fabrication tool of making, and the formed channel part of fabrication tool of making by photoetching process can have basically trapezoidal transverse cross-sectional area.Be used to form have basically circular transverse cross-sectional area, the additive method of the channel part of trapezoidal transverse cross-sectional area or shape of cross section also is fine basically.Than the channel part of the first assembly, can form with the fabrication tool of making by identical or different method the second channel part of the second assembly, and/or the second channel of the second assembly part can have identical or different shape of cross section.
As described here, in certain embodiments, before the user used first, the passage of the first assembly of box did not have fluid to be communicated with the passage of the second assembly of box.For example, even after two assemblies cooperate, be schematically shown such as Fig. 9 D, passage 206 does not have fluid to be communicated with passage 207 mutually yet.But box can further comprise miscellaneous part or the assembly that the first assembly 20B and/or the second assembly 20C can be attached to other parts of box, for example fluid connector alignment member 202(Fig. 9 E).As described here, the fluid connector alignment member can be configured to containing fluid connector 220 and be mated, this can allow respectively the passage 206 of the first assembly and the second assembly to be communicated with fluid between the passage 207.For example, fluid connector can comprise fluid path, fluid path comprises fluid path entrance and fluid path outlet, wherein the fluid path entrance can be by being fluidically connected to the outlet of passage 206, and the fluid path outlet can be by the entrance (vice versa) that is fluidically connected to passage 207.The fluid path of fluid connector can have any suitable length for interface channel (for example, at least 1cm, at least 2cm, at least 3cm, 5cm at least).Fluid connector can be a standby part together with box, and is packaged as so that fluid connector does not pass through fluid mode interface channel 206 and passage 207.
About the assembly of box or box, fluid connector can have any suitable configuration.Be schematically shown such as Fig. 9 E, when fluid connector is connected to box, fluid connector can be arranged on a side relative with another assembly (for example, assembly 20C) of assembly (for example, assembly 20B).In other embodiments, fluid connector can be arranged between two assemblies of box.For example, fluid connector can be arranged on assembly or the layer of (for example, being clipped in the middle) between two assemblies of box.Other configurations also are fine.
Additionally, fluid connector can be placed as the one or more assemblies or the layer that are substantially perpendicular to box, for example, be schematically shown such as Fig. 9 E.In other embodiments, fluid connector can be placed as and be arranged essentially parallel to one or more assemblies of (for example, at the top or level relative) box.Other configurations also are fine.
In some cases, alignment member and/or fluid connector are connected to only assembly of multicompartment box at entity, and in other cases, alignment member and/or fluid connector are connected to a plurality of assemblies of multicompartment box at entity.In certain embodiments, the part of assembly that is connected to the box of alignment member and/or fluid connector at entity has certain thickness, to allow suitable connection.For example, when fluid connector was designed to insert the entrance and exit of passage of box, box can have the necessarily thickness of (for example, minimum) inserting the zone.Be designed for the location that is connected with fluid connector, one or more assemblies of box or box for example can have at least 1cm, at least 1.5cm, at least 2cm, at least 2.5cm, at least 3cm, at least 4cm or the thickness of 5cm at least.Be not that other parts (the perhaps assembly of box) of being designed for the box that is connected with alignment member and/or fluid connector for example can have less than 5cm, less than 4cm, less than 3cm, less than 2.5cm, less than 2cm, less than 1.5cm, less than 1cm, less than 0.5cm or less than the thickness of 0.1cm.
Comprise one or more the have assembly of channel network or the boxes of layer although a lot of descriptions are here pointed to, in other embodiments, box can comprise more than 2, more than 3, more than 4 such assembly or layer.For example, be schematically shown such as Fig. 9 F, box can comprise assembly 20B, 20C, 20D and 20E, and each assembly comprises at least one passage or channel network.In some cases, one or more assemblies (for example, 2,3 or all components) passage (a plurality of passage) before using first, can not connect by the fluid mode, but when using first, can connect by the fluid mode (for example by using fluid connector).In other embodiments, the passage of one or more assemblies (for example, 2,3 or all components) connected by the fluid mode before using first.
As described here, each assembly of box or layer can be designed to have the specific function different from the function of other assemblies of box.In other embodiments, two or more assemblies can have identical function.For example, shown in the illustrative examples of Fig. 9 F, each assembly 20C, 20D and 20E can have a plurality of measured zone 209 connected in series.When fluid connector is connected to compound box, the each several part of sample (or a plurality of sample) can be introduced the channel network among each assembly 20C, 20D and the 20E, to carry out a plurality of analyses.
In certain embodiments, at least the first of box the assembly and the second assembly can be for device or the equipment of determining specific chemistry or biology condition.Device or equipment for example can comprise the first assembly, and the first assembly comprises the first passage that forms with the first material, and first passage comprises entrance, outlet and has at least one part greater than 200 microns cross sectional dimensions at the first entrance and between exporting.Device or equipment also can comprise the second assembly, and the second assembly comprises the second channel that forms with the second material, and second channel comprises entrance, outlet and has at least one part less than 200 microns cross sectional dimensions at the second entrance and between exporting.In some cases, will install or equip and be packaged as so that the first assembly and the second assembly interconnect.For example, the first assembly and the second assembly can integrally interconnect.In other embodiments, the first assembly and the second assembly reversibly interconnect.Device or equipment can further comprise fluid connector, be used for connecting first passage and second channel by the fluid mode, fluid connector comprises fluid path, fluid path comprises fluid path entrance and fluid path outlet, wherein the fluid path entrance can be by being fluidically connected to the outlet of first passage, and the fluid path outlet can be by being fluidically connected to the entrance of second channel.In certain embodiments, with device or equipment is packaged as so that fluid connector does not connect first passage and second channel in the packing by the fluid mode.When prospective users first during operative installations, fluid connector be can be used for so that the mutual fluid of first passage and second channel is communicated with.
As described here, install or be equipped in and to comprise mutually different channel part on the different assemblies of box.Therefore, in certain embodiments, device comprises one or more following characteristics: the first material that is used to form the first passage part of the first assembly is different from the second material of the second channel part that is used to form the second assembly; The shape of cross section of first passage part is different from the shape of cross section of second channel part; And/or the rms surface roughness of first passage part is different from the rms surface roughness of second channel part.Channel part also can have as described herein other differences.
Box described here can have any suitable volume, is used for carrying out the analysis of chemistry for example and/or biological respinse or other processing.The whole volume of box for example comprises any reagent storage zone, measured zone, liquid containing zone, refuse is regional and any fluid connector and fluid passage associated with it.In certain embodiments, use reagent and sample in a small amount, and the whole volume of fluid means is for example less than 10mL, 5mL, 1mL, 500 μ L, 250 μ L, 100 μ L, 50 μ L, 25 μ L, 10 μ L, 5 μ L or 1 μ L.
Box described here can be portable, and hands in certain embodiments.The length of box and/or width for example can be less than or equal to 20cm, 15cm, 10cm, 8cm, 6cm or 5cm.The thickness of box for example can be less than or equal to 5cm, 3cm, 2cm, 1cm, 8mm, 5mm, 3mm, 2mm or 1mm.Preferably, portable unit is applicable to instant monitoring installation.
Should be appreciated that box described here and their each assembly are exemplary, and can use other configurations of box and assembly and/or box and the assembly of other types by system and method described here.
Described system and method can relate to various dissimilar analyses, and can be used for determining various sample.In some cases, analysis relates to chemistry and/or biologically.In certain embodiments, chemistry and/or biological respinse relate to combination.In the described box dissimilar combinations can occur here.In conjunction with can relate to the corresponding molecule that shows mutual attraction or binding ability between interaction, typical specific or unspecific combination or interaction comprise that biochemistry, physiology and/or materia medica interact.Bioconjugation define equimoleculars such as comprising protein, nucleic acid, glycoprotein, carbohydrate, hormone between the interactional type that occurs.Particular example comprises additional part, protein/nucleic acid repressor/inducer, ligand/cell surface recipient, virus/ligand of antibody/antigen, antibody/haptens, enzyme/substrate, enzyme/inhibitor, enzyme/prothetic group, conjugated protein/substrate, carrier protein/substrate, hemagglutinin/carbohydrate, recipient/hormone, recipient/effector, nucleic acid etc.In conjunction with also can between protein or other compositions and cell, occurring.In addition, device described here can be used for other fluid analysis (can relate to or can not relate in conjunction with and/or react), for example detection of composition, concentration etc.
In some cases, heterogeneous reaction (or chemical examination) can occur in box; For example, binding partner can be associated with the surface of passage, and complementary binding partner can appear in the fluid-phase.Also can relate to other solid-phases chemical examinations of the compatible reaction between the molecule of protein or other biological molecule (for example, DNA, RNA, sugar) or non-Lock-in.The non-limiting example of the typical reaction that can carry out in box comprises chemical reaction, enzyme reaction, based on the reaction (for example Ag-Ab) of immunity and based on the reaction of cell.
Use box described here can determine that the non-limiting example of the analyte of (for example, detecting) comprises specified protein, virus, hormone, medicine, nucleic acid and polysaccharide; Specific antibodies, for example HTLV-I, HIV, A type hepatitis, viral hepatitis type b and non-A type/non-B hepatitis, rubella, measles, human parvovirus B19, mumps, malaria, varicella or leukemic IgD, IgG, IgM or IgA immunoglobulin (Ig); Humans and animals hormone, for example thyrotropic hormone (TSH), thyroxine (T4), metakentrin (LH), follicle-stimulating hormone (FSH) (FSH), testosterone, progesterone, human chorionic gonadotropin, estradiol; Other protein or peptide, for example Troponin I, CRP, myoglobin, brain sodium protein, prostate specific antigen (PSA), free PSA, composite PSA, pro-PSA, EPCA-2, PCADM-1, ABCA5, hK2, beta-MSP(PSP94), AZGP1, annexin A 3, PSCA, PSMA, JM27, PAP; Medicine, for example paracetamol or theophylline; Labeling nucleic acid, for example PCA3, TMPRS-ERG; Polysaccharide for example is used for the cell surface antigen of HLA tissue typing and bacterial cell wall material.Detectable chemicals comprises explosive (for example TNT), never poison and environmentally harmful compound, for example Polychlorinated biphenyls (PCB), dioxy (mixing) glutinous rehmannia, hydro carbons and MTBE.Typical sample fluid comprises physiological fluid, for example human or animal's whole blood, serum, blood plasma, seminal fluid, tears, urine, sweat, saliva, cerebrospinal fluid, vaginal fluid; The external fluid or the environment liquid that use in the research are for example suspected the water liquid that analyte pollutes.
In certain embodiments, before using first, will can be used for determining in the passage or chamber of one or more reagent storage at box with the analyte (for example, the binding partner of the analyte that determine) of sample, specifically to test or to chemically examine.Analyzing in the situation of antigen, corresponding antibody or fit can be the binding partner that is associated with the surface of microfluidic channel.If antibody is analyte, then suitable antigen or fit can be the binding partner that is associated with the surface.When determining disease condition, preferably antigen is placed the surface, and test the antibody that in object, has produced.This antibody for example can comprise HIV antibody.
In certain embodiments, with the box adjustment and arrange to analyze, analyze to relate to and accumulate opaque material in the zone of microfluidic channel, be exposed to this zone under the light and the transmission of definite light by opaque material.Opaque material can comprise the material that affects the transmissivity of light under one or more wavelength.Opaque material is not refracted ray only, but for example by absorbing or reflection ray, reduces transmission by the amount of material.The difference amount of different opaque materials or opaque material can allow transmissivity for example to illuminate opaque material less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 1% light.The example of opaque material comprises molecular layer, ceramic layer, polymer layer and the opaque material layer (for example dyestuff) of metal (for example, metal element).In some cases, opaque material can be the metal of electroless deposition.These metals for example can comprise silver, copper, nickel, cobalt, palladium and platinum.
The opaque material that forms passage can comprise one group of discontinuous individual particles of common formation opaque layer, but in one embodiment, opaque material is the continuous material of taking the general closed planar shape.Opaque material for example can have more than or equal to 1 micron, more than or equal to 5 microns, greater than 10 microns, more than or equal to 25 microns or more than or equal to 50 microns size (for example width of length).In some cases, opaque material extends across the width (for example, measured zone) of the passage that comprises opaque material.Opaque layer for example can have and is less than or equal to 10 microns, is less than or equal to 5 microns, is less than or equal to 1 micron, is less than or equal to 100 nanometers or is less than or equal to the thickness of 10 nanometers.Even under these little thickness, also can detect transmission change.When comparing with the technology that does not form opaque layer, opaque layer can improve chemical examination sensitivity.
In one group of embodiment, box described here is used for carrying out immunoassays (for example being used for human IgG or PSA), and optionally, uses the silver that is used for the signal amplification to strengthen.In this immunoassays, after the pattern delivery that will comprise human IgG arrives reflecting point or analyzed area, the combination between human IgG and the anti-human IgG can occur.One or more reagent that can optionally be stored in before using in the passage of device can overflow the pairing complex of this combination.One of them of the reagent of storage can comprise specially and the solution of the metallic colloid of antigen (for example human IgG) combination to be detected (for example, gold pairing antibody).This metallic colloid can provide catalyst surface, is used for opaque material, for example metal level (for example silver) in the deposition on analyzed area surface.By using the binary system: metal precursor (for example solution of silver salt) and reducing agent (for example, hydroquinones, chlorine are to stupid diphenol, pyrogaelol, metol, 4-amino phenols and phenidone), can form metal level, alternatively, before using, two kinds of compositions can be stored in different passages.
When plus or minus pressure differently was applied to system, silver salt and reductant solution can mix at them (for example, because diffusion) in passage passage crosspoint merged, then the Spillover Analysis zone.Therefore, if antibody-antigen is in conjunction with appearing in the analyzed area, owing to the existence of the catalyst metals colloid that is associated with antibody-antigenic complex, metal precursor solutions flows through the formation that this zone can cause opaque layer, for example silver layer so.Opaque layer can be included in the material that affects the transmissivity of light under one or more wavelength.For example by than the reduction of a part of area measure that does not comprise antibody or antigen by the light transmittance of a part of analyzed area (for example, the tortuous passageway zone), can detect the opaque layer that in passage, forms by optical mode.Alternatively, when in analyzed area, forming film, by the variation of measurement as the light transmittance of the function of time, can picked up signal.When comparing with the technology that does not form opaque layer, opaque layer can improve chemical examination sensitivity.Additionally, can use and (for example produce optical signal, absorptivity, fluorescence, luminous or flash of light chemiluminescence, electrogenerated chemiluminescence), the signal of telecommunication (for example, process resistance or the electrical conductivity of the metal structure that produces by electroless coating) or magnetic signal is (for example, magnetic bead) various amplification chemistry are to allow by the detector detection signal.
Can use various types of fluids by box described here.As described here, fluid can be introduced box when using first, and/or is stored in the box before using first.Fluid comprises liquid, for example solvent, solution and suspension.In addition, fluid comprises the mixture of gas and gas.When comprising multiple fluid in the box, can fluid be separated by one other fluid, one other fluid is preferably in every kind of fluid of the first two fluid can not mix in fact.For example, if passage comprises two kinds of different aqueous solution, then the splitter of the 3rd fluid can be immiscible in fact in two kinds of aqueous solution.When the aqueous solution will keep separating, the immiscible in fact fluid that can be used as separator can comprise gas (for example air or nitrogen) or detest aqueous fluid, detests aqueous fluid and can not mix with the aqueous solution in fact.In addition, can select fluid based on the reaction of fluid and adjacent fluid at least in part.For example, can use in certain embodiments inert gas (for example nitrogen), inert gas can help to keep and/or stablize any adjacent fluid.Example for separating of the immiscible in fact fluid of the aqueous solution is perfluorodecalin.Also can select the separator fluid based on other factors, comprise any impact that the separator fluid may produce the surface tension of adjacent fluid post.Preferably with the surface tension in any fluid column maximization, in the situation that changes environmental condition (for example vibrate, vibrations and variations in temperature), to promote the maintenance as the fluid column of single sequential cells.For the reflecting point that fluid is provided to it (for example, measured zone), the separator fluid also can be inertia.For example, if reflecting point comprises the bioconjugation partner, then separator fluid (for example air or nitrogen) is on almost not impact or not impact of binding partner.If the liquid that comprises in the device is owing to expand or shrink such as temperature (comprise and freezing) or the such variation of pressure variation, also can be provided for the space expanded in the passage of fluid means as the use of the gas (for example air) of separator fluid so.
Following described in more detail, microfluid sample analysis device 100 for example can comprise Fluid Flow in A source 40(, control pressurer system), passage can by being fluidically connected to passage 206,207,222, be passed through to exert pressure mobile sample and/or other reagent to passage in Fluid Flow in A source 40.Especially, Fluid Flow in A source 40 can be configured at the beginning sample and/or reagent are moved to the first passage 206 from the passage 222 of U-shaped basically.In addition, Fluid Flow in A source 40 can be used for the reagent in the second channel 207 is moved through the passage 222 of U-shaped basically and enters first passage 206.Sample and reagent by measured zone 209 and analyzed after, Fluid Flow in A source 40 can be configured to fluid is moved in the absorbent material 217 of box 200.In one embodiment, the Fluid Flow in A source is vacuum system.But should be appreciated that and to use other Fluid Flow in A sources, for example valve, pump and/or other assemblies.
The top view of box 20 illustrates above-mentioned a lot of assembly among Fig. 9 A, except in the present embodiment, the passage 206,207 in the cassette housing is different from outside schematic diagram shown in Figure 8 is configured.In one embodiment, cassette housing comprises and being configured to and interactional at least one surface of microfluid sample analysis device, therefore box can be inserted analyzer and is retained in wherein.In one embodiment, shown in Fig. 9 A, shell comprises along the cam face of box 20 sidepieces.In this particular example, cam face is included in the recess 230 that box 20 1 ends form.The other end of box 20 comprises angle of bend surface 232.Following described in more detail, this cam face of box can be configured to interact with sample analysis device 100, so that analyzer 100 can detect existence and/or the position of box 20 in analyzer 100 of box 20 in the shell 10.Especially, the angle of bend surface configuration can be a part of analyzer of contact, arm for example, and can be with recess configuration for keeping this part of analyzer, thereby box is remained in the analyzer.
The below discusses the intraware of sample analysis device 100 with reference to Figure 10 to Figure 12.Figure 10 to Figure 12 from assembled view, illustrate box 20 inserted opening 120 in the shells.In one embodiment, shell 101 comprise be configured to box on interface and the assembly that engages of matable assembly.In the embodiment that this illustrates especially, shell 101 comprises the arm 121 that is arranged in the shell, and it is configured to engage the cam face on the above-mentioned box.In primary importance, arm 121 extends in the opening 120 in the shell at least in part, so that when box 20 inserts opening 120, arm is pushed the second place from opening 120, allows box 20 to enter opening 120.
Arm 121 can be configured to the side surface of contact box when box inserts opening 120.Shown in Fig. 9 A, the end of box 20 can comprise curved surface 232, and the side surface that curved surface 232 can be arm 121 contact boxes provides level and smooth transition.In one embodiment, arm 121 is connected to spring 122, forms spring-loaded arm, therefore when box is in analyzer 100, so that it pushes down the side surface of box.Especially, spring-loaded arm is pushed rearward, and in fact pushes in certain embodiments primary importance.In one embodiment, the end of arm 121 comprises the cylinder 124 that engages with the side surface of box 20.Cylinder 124 can be configured to when with the box insertion position minimum friction forces between two assemblies.Such as Figure 11 and shown in Figure 12, in case arm 121 engages with recess 230, owing to the biasing of spring 122, just arm 121 is back into its initial position.In case arm 121 and this inside cam just box 20 are arranged and is retained in the shell 10 of analyzer 100, and the biasing of spring 122 prevent that box 20 from skidding off analyzer.
Should be appreciated that the box 20 that the recess 230 on spring-loaded arm 121 and the box 20 in the analyzer 100 can be configured to detect and arrange in the analyzer.As described below, it should also be appreciated that this disposing helps indicate box 20 correctly to be arranged in the analyzer and be ready to analyze and process to the user.After analyzing, the user can by box 20 is released opening 120, remove box 20 from analyzer 100.Power and/or analyzer 100 that the user can apply the biasing that overcomes spring 122 can dispose the unlocking structure (not shown), and arm 121 is moved into its second places, so that it no longer contacts with recess 230 on the box 20.
In one embodiment, when the roller 124 on the electronic position switch indication arm 121 is pushed into its second place (for example, when box 20 is inserted into analyzer).The electronic position switch also can indication roller when towards/return (for example, perhaps when not having box in the analyzer, perhaps when box is fully inserted into analyzer and roller and is bonded in the recess 230) to its initial position.When another position switch can be configured to indication inserts box fully and correctly is arranged in the analyzer 100.Therefore, switch can be used for indicating box 20 correctly to be arranged in the analyzer to the user.Various these box sensors 410 are discussed in more detail below shown in the schematic diagram shown in Figure 16.
A lot of machineries and mechanical ﹠ electrical technology can be used for loading and unloading reliably box.For example, disc (disc that for example finds in CD Player) can clamping box and the analyzer of coming in and going out that slides.Can realize this slip (for example, directly drive disc or utilize pulley) by hand or by motor.Another example of loading and unloading box comprises uses the motorised units that contacts with the box entity.For example, motorised units can cooperate with box by friction one or more sides of box and/or top and/or bottom.In some cases, this unit can cooperate with box by the gear of making in box one side.
In addition, Figure 10 illustrates passage 206(and the passage 207 that can be configured in the box 20, if it is by being fluidically connected to 206) exert pressure, with the part of mobile sample by the Fluid Flow in A source 40 of passage.Figure 15 also illustrates Fluid Flow in A source 40.In an illustrative examples, Fluid Flow in A source 40 is vacuum systems and comprises vacuum source or pump 42, two V-RSR Vacuum Reservoirs 44 that can separate by vacuum governor 46,45 and manifold 48, and manifold 48 provides V-RSR Vacuum Reservoir to be connected with fluid between the box 20.In addition, manifold 48 comprises that the one or more fluids that are connected with one or more ports on the box connect.For example, manifold can provide port 213 to be connected with fluid between the valve (for example solenoid valve).In certain embodiments, open and close this valve and can control air and enter wherefrom box, therefore serve as gas valve.
As mentioned above, in one embodiment, vacuum source 42 is pumps, for example solenoid operated membrane pump.In other embodiments, the making of pump that can be by other types or Fluid Flow in A source drives/the control Fluid Flow in A.For example, in one embodiment, by edge direction pushing syringe plunger outwardly, can produce vacuum with syringe pump.In other embodiments, apply normal pressure at one or more entrances of box, so that the Fluid Flow in A source to be provided.
In certain embodiments, when when applying the non-zero pressure drop (that is, Δ P) of substantial constant between the entrance of box and the outlet, Fluid Flow in A occurs.In one group of embodiment, when when applying the non-zero pressure drop (that is, Δ P) of substantial constant between the entrance of box and the outlet, all analyze.For example, by applying normal pressure at entrance, perhaps apply lower pressure (for example, vacuum) in outlet, can obtain the non-zero pressure drop of substantial constant.In some cases, when the Fluid Flow in A master if it were not for occur by capillary force and/or in the situation of not using actuated valve (for example, in the situation of the cross-sectional area of the passage of the fluid path that does not change box), obtain the non-zero pressure drop of substantial constant.In certain embodiments, basically during whole analysis of in box, carrying out, for example, respectively in the outlet downstream of the entrance (can be connected to fluid connector) of measured zone and measured zone (for example, the outlet downstream in liquid containing zone) between, the non-zero pressure drop of substantial constant can appear.
In one embodiment, vacuum source is configured to apply pressure to approximately-atmospheric pressure of 60kPa(about 2/3 to passage).In other embodiments, vacuum source is configured to apply pressure to approximately-30kPa to passage.In certain embodiments, vacuum source is configured to passage exert pressure for example arrive 100kPa and-70kPa between ,-70kPa and-50kPa between ,-50kPa and-20kPa between or-20kPa and-1kPa between.
As mentioned above, in one embodiment, can provide two V-RSR Vacuum Reservoirs 44,45.Pump can be opened, so that apply pressure to approximately-60kPa to the first reservoir.The adjuster 46 that is arranged between the reservoir 44 and 45 can guarantee only to apply pressure to different pressure to the second reservoir 45, for example approximately-and 30kPa.This adjuster can remain on the pressure of reservoir 45-30kPa(or remain on another suitable pressure), as long as another reservoir 44 remains on certain pressure limit, for example-60kPa and-30kPa between.Pressure sensor can be monitored the pressure in each reservoir 44,45.If the pressure in the first reservoir 44 reach set point (for example approximately-40kP), just can start pump, to reduce the pressure in the first reservoir 44.The second reservoir 45 can be configured to detect any leakage in the whole vacuum system 40.As shown in figure 15, vacuum system 40 can comprise and is couple to reservoir 44,45 filter 58.Solenoid valve 59 can be served as the gas valve that is connected to port 213 by manifold.
In case box 20 is arranged in the analyzer 100, just Fluid Flow in A source 40 can be connected to box 20, connect to guarantee Fluid Sealing.As mentioned above, box 20 can comprise port 219, and port 219 is configured to passage 206 is connected with Fluid Flow in A source 40, and if passage 207 by being fluidically connected to passage 206, then passage 207 is connected with Fluid Flow in A source 40.As shown in figure 14, in one embodiment, seal or O shape ring 52 is arranged on around the port 219, and linear solenoid 50 is arranged on O shape encircles 52 tops, to push down and to seal O shape ring with respect to box body 200.As shown in figure 14, manifold adapter 54 can be arranged between linear solenoid 50 and the manifold 48, and passive reset spring 56 is arranged on around the manifold 48, when solenoid does not charge, to promote manifold away from box body 200.In one embodiment, a plurality of ports on the box 20 can with manifold 48 interfaces.For example, shown in the exemplary embodiment shown in Fig. 9 A, except port 219, two blow vents 215 and a Hybrid port 213 can also be arranged.Interface between each port and the manifold can be independently (for example, can not have fluid to connect in manifold inside).
In one embodiment, when starting Fluid Flow in A source 40, can exert pressure to the passage 206,207 in the box 20 that (for example arrive approximately-30kPa), this can be to the fluid (fluid sample and reagent) in the outlet driving passage.In the embodiment that comprises blow vent 215 and Hybrid port 213, the gas valve 59 that is connected to port 213 by manifold 48 can be opened first, so that whole reagent in Hybrid port 213 downstreams are mobile to outlet, but can not cause the reagent of Hybrid port 213 upstreams to move.In case gas valve is closed, the reagent of Hybrid port 213 upstreams just can move to Hybrid port, and is then mobile to outlet.For example, fluid can be stored in the passage of Hybrid port upstream continuously, and close after the gas valve of channel setting, fluid can flow to channel outlet successively.In some cases, can be with fluid storage separately and in the passage that intersects, and after closing gas valve, fluid can flow to the crosspoint together.This group embodiment for example can be used for controllably mixing them when fluid flows together.The volume of the timing that transmits and the fluid of transmission for example can be controlled by the timing that gas valve starts.
Preferably, can in the situation of the cross section that does not compress the microfluidic channel that gas valve operates, operate gas valve, the situation that can occur as some valve in the prior art.This operator scheme is effective for the leakage that prevents valve.In addition, because can use gas valve, so some system and methods described here do not need to use some internal valves, for example since the price of internal valves high, make complicated, fragile, with the limited compatibility of the gas that mixes and liquid system and/or the unreliability in microfluid system so that internal valves has problem.
Although should be appreciated that and described gas valve, system and method described here also can use the valve mechanism of other types.The non-limiting example of the valve mechanism that can be associated with valve in operation comprises diaphragm valve, ball valve, gate valve, butterfly valve, globe valve, needle valve, pinch valve, lift valve or pinch valve.Can be by any suitable mode actuating valve mechanism, comprise solenoid, motor, by hand, start or by hydraulic pressure/blast by electronics.
As mentioned above, the whole liquid in the box 20 (sample and reagent) can move in the liquid containing zone, and the liquid containing zone can comprise absorbent material 217.In one embodiment, an absorbent material liquid-absorbing, so gas can flow out box by outlet.
Can use and variously determine (for example, measure, quantitatively, detect and restriction) technology, other compositions or the condition coming analyzing samples composition for example or be associated with microfluid system described here or box.Determine that technology can comprise the technology based on optics, for example light transmission, light absorption, light scattering, light reflection and vision technique.Determine that technology also can comprise luminescence technology, for example luminescence generated by light (for example fluorescence), chemiluminescence, bioluminescence and/or electrochemical luminescence.In other embodiments, determine that technology can measure conductivity or resistance.Therefore, analyzer can be configured to the detection system that comprises that these and other are suitable.
Different optical detective technologies provides multiple choices for determining reaction (for example chemical examination) result.In certain embodiments, the measurement result of transmissivity or absorptivity means and can detect light by identical wavelength by the wavelength that sends from light source with light.Although light source can be with the luminous narrow-band source of single wavelength, it also can be wide range source luminous in a wave-length coverage, because a lot of opaque material can stop the wavelength of wide region effectively.In certain embodiments, can come operating system with minimum Optical devices (for example, the fluorescence detector of simplification).For example, determine that device can not need photoelectric multiplier, can not need wavelength selector (for example grating, prism or filter), can not need to guide or the device (for example focalizer) of focused ray, perhaps can not need to amplify optics (for example, lens).Cancel or reduce these parts and can obtain more cheap, more durable device.
Figure 10 to Figure 14 illustrates the example optical system 80 in the shell 10 that can be arranged on analyzer 100.Illustrate such as these embodiment, optical system 80 comprises the first light source 82 and the detector 84 that separates with the first light source at least.The first light source 82 can be configured to when box inserts analyzer 100, make light pass through the first measured zone of box 20.The first detector 84 can be set to relative with the first light source 82, to detect the light quantity through the first measured zone of box 20.Schematically show such as Figure 11 and Figure 12, in one embodiment, optical system comprises 10 light sources and 10 detectors.Should be appreciated that in other embodiments the quantity of light source and detector can change, because the invention is not restricted to this.As mentioned above, box 20 can comprise a plurality of measured zone 209, and box 20 can be arranged in the analyzer, so that each measured zone 209 alignment light source and corresponding detector.In certain embodiments, light source comprises optical aperture 83(Figure 11), optical aperture 83 can help light is directed to specific region the measured zone of box from light source.
In one embodiment, light source is light emitting diode (LED) or laser diode.For example, can use the InGaAlP red semiconductor laser diode of emission 654nm light.Also can use other light sources.Schematically show such as Figure 14, light source can be arranged in nest (nest) or the shell 90.Nest or shell 90 can comprise narrow hole or tubule 92, can help to calibrate light.As shown in the figure, light source can be arranged on the top, position that box 20 inserts analyzer, so that light source is luminous at the upper surface of box 20 downwards.Light source is also passable with respect to other suitable configurations of box.
The wavelength that should be appreciated that light source can change, because the invention is not restricted to this.For example, in one embodiment, the wavelength of light source approximately is 670nm, and in another embodiment, the wavelength of light source approximately is 650nm.Should be appreciated that in one embodiment the wavelength of each light source can be different, so each measured zone 209 of box receives different optical wavelength.In a particular embodiment, when measuring packed cell volume or hemoglobin, can with about 590nm with approximately between the 805nm etc. absorbing wavelength (isobestic wavelength) scope at least one of measured zone.
As mentioned above, detector 84 and light source 82 can be separated and are arranged on the light source below, to detect the light quantity by box.In one embodiment, one or more detectors are photoelectric detector (for example, photodiodes).In certain embodiments, photoelectric detector can be any appropriate device of the transmissivity of the light that can detection light source sends.One type of photoelectric detector is the optical integrated circuit (IC) that is included in photodiode, amplifier and voltage regulator that 700nm has peak sensitivity.As shown in figure 14, detector can be arranged in nest or the shell 94, nest or shell 94 can comprise narrow hole or tubule 96, to guarantee that 84 measurements of detector are from the light at measured zone 209 centers.Following described in more detail, if light source is impulse modulation, then photoelectric detector can comprise wave filter, is not the impact of selecting the light of frequency with elimination.When detecting a plurality of adjacent signal simultaneously, can save in the light source of each measured zone (for example, surveyed area) in the frequency downconverts of the frequency of the contiguous light source that fully is different from it.In this configuration, can (for example, use software) each detector configurations is selected for the light source under it, thereby avoid interfering the light that matches from adjacent optical.
Therefore as described here, box can comprise measured zone, and measured zone comprises bending channel, and bending channel is configured and is arranged as the aligning detector, and on time, detector can be measured the individual signals more than one adjacent segment by bending channel.In certain embodiments, detector can detect the signal of an above fragment at least a portion zone of bending channel and by bending channel, and first's class signal of therefore measuring from the first fragment of bending channel is similar to the second portion signal of measuring from the second fragment of bending channel.In these embodiments, because signal is represented as the part more than one fragment of bending channel, so do not need accurate aligning the between detector and the measured zone.
Detector in measured zone (for example, bending area) not needing accurate location on is an advantage, because need to be such as the equipment (although can use them in certain embodiments) of the such outside of microscope, lens and alignment stage (and might be expensive).On the contrary, can be by not necessarily needing the user initiatively or the cost effective method of independent alignment procedures is aimed at.For example, in one embodiment, the box that comprises bending area can be placed in the groove of analyzer described here (for example, being placed on box has in the chamber of same or similar shape), and can automatically measured zone be placed in the light beam of detector.For example since box with respect to the variation of box, box in groove accurate location and the possible cause of the misalignment due to the normal use of box can ignore than the size of measured zone.As a result, bending area can remain in the light beam, and can be owing to these variations are interrupted detecting.
Detector can detect the signal in all or part of measured zone (for example, comprising bending area).In other words, the bending area of difference amount can be used as optical detection path.For example, detector can detect the signal in the measured zone (but be less than measured zone 100%) of at least 15% measured zone, at least 20% measured zone, at least 25% measured zone, at least 50% measured zone or at least 75%.The opacity that wherein measured zone is for example also depended on the material of making passage as the zone of optical detection path (for example; whether the whole or part of passage transparent), can cover the amount use of over cap (for example, via) of the opaque material of portion of channel and/or the size of detector and measured zone.
In one embodiment, the signal that the reaction of carrying out in the box produces is connatural in whole measured zone (for example, on whole bending channel zone).That is to say that measured zone (for example, bending channel zone) can allow when carrying out chemistry and/or biologically (and for example when detecting by detector) this region generating and/or detect single congeniality signal.Before in the bending channel zone, reacting, to be detected/definite single kind (and concentration of kind) that bending channel for example can comprise.This kind can be absorbed the surface of bending channel.In another embodiment, signal is congeniality on the bending area part only, and one or more detector can detect the unlike signal in each part.In some examples, can an above measured zone is connected in series, and with each measured zone for detection of/determine different kinds.Although should be appreciated that and described bending area, also can use the measured zone that does not comprise bending area.
The applicant has realized that the output optical transmission by the measured zone of box can be used for not only determining the information about sample, and determines the information (for example, the mixing of reagent, flow rate etc.) of the particular procedure that occurs in the fluid system about box.In some cases, the measurement of the light by the zone can be used as the feedback of Fluid Flow in A in the control system.In certain embodiments, can determine unusual in the operation of quality control or box.For example, it is unusual that the feedback from the measured zone to the control system can be used for determining having occurred in the microfluid system, and control system can be to one or more assembly transmitted signals, so that all or part of of system closed.Therefore, use system and method described here can control the quality of ongoing processing in the microfluid system.
Will be appreciated that clear liquid (for example water) can allow a large amount of light to be transferred to detector 84 from light source 82 by measured zone 209.Compare when clear liquid is arranged, the air in the measured zone 209 can cause less light transmission by measured zone 209, because more light may scattering in passage.When blood sample is in measured zone 209, because light is by the blood cell scattering and owing to absorbing, so significantly less light quantity can be passed through detector 84.In one embodiment, silver be attached to measured zone in the sample composition on surface be associated, and when silver-colored when piling up in measured zone 209, light transmission less and less is passed through measured zone 209.
Have realized that and measure in light quantity that each detector 84 detects so that the user can determine which kind of reagent is arranged in specific measured zone 209 at specific time point.Have realized that in addition the light quantity that detects by measuring each detector 84, just can measure the silver amount of deposition in each measured zone 209.This amount can corresponding to the amount of the analyte of catching between the stage of reaction, therefore can provide the measurement of the concentration of analyte in the sample like this.
As mentioned above, the applicant has realized that optical system 80 can be used for various quality control reasons.At first, sample arrival measured zone (wherein, optical system detection is by the light of measured zone) institute's time spent can be used for determining whether system have leakage or obstruction.In addition, when the expectation sample has certain volume (for example about 10 microlitres), about being coupled to sample by the expectation flowing time of passage and measured zone.If sample is not in expectation flowing time scope, it can be indicated does not have enough samples to analyze and/or the sample of type of error is loaded into analyzer.Additionally, can determine based on the type (for example, blood plasma, blood, urine etc.) of sample result's expected range, and if sample not in expected range, just can misdirection.
In one embodiment, optical system 80 comprises a plurality of light sources 82,86 and the detector 84,88 of a plurality of correspondences.Be schematically shown such as Figure 11 to Figure 13, in one embodiment, the first light source 82 is adjacent with secondary light source 86, and wherein the first light source 82 is configured to make light to pass through the first measured zone of box 20, and secondary light source is configured to make light to pass through the second measured zone of box 20.In one embodiment, close the first light source 82 unless light source is configured such that, otherwise do not start secondary light source 86.The applicant has realized that some light from a light source can be spread to adjacent detector, and can affect the light quantity that detects in adjacent detector.In one group of embodiment, if adjacent light source starts when the first light source starts, then the first measured zone of box and the light quantity of the second measured zone are passed through in two detectors 84,88 simultaneously measurements, and this can cause incorrect measurement result.
Therefore, in one group of embodiment, a plurality of light sources are configured to continuously, once only start a light source.So the corresponding detector that is used for the light source of startup only detects the light quantity by corresponding measured zone 209.In a particular embodiment, light source is configured to (for example start respectively the short time cycle, at least be about 500,250,100 or 50 microseconds, perhaps in certain embodiments, be less than or equal about 500,250,100 or 50 microseconds), and adjacent light source is configured to start similar time range.Continue the startup of 100 microseconds corresponding to the speed of 10KHz.In one embodiment, a plurality of analog-digital converters are used for driving light and per 500,250,100 or 50 microseconds and measure the light quantity that detects at each corresponding detector.Thereby driving in this way light can help prevent scattered light by the light quantity that detect of a measured zone change by adjacent measured zone.
Although the benefit that may have some to be associated with driving light source by the way will be appreciated that to the invention is not restricted to this, and other arrange also can, for example can start simultaneously a plurality of light sources.For example, in one embodiment, can basically drive simultaneously the not light source of direct neighbor.
With reference to Figure 17, in one embodiment, analyzer 100 comprises the humidity control system that is arranged in the shell 101, and it can be configured to regulate the temperature in the analyzer.For some sample analysis, may in certain temperature range, keep sample.For example, in one embodiment, wish the temperature in the analyzer 100 is remained on about 37 ° of C.Therefore, in one embodiment, humidity control system comprises the heater 140 that is configured to heat box 20.In one embodiment, heater 140 is resistance heaters, and resistance heater can be arranged on the downside of placing the position of box 20 in the analyzer 100.In one embodiment, humidity control system also comprises electro-hot regulator 142 and controller circuitry, and electro-hot regulator 142 is used for measuring the temperature of box 20, and controller circuitry can be set to control temperature.
In one embodiment, if necessary, the passive mobile air that can be used in the diagnosis refrigeration device of analyzer Air.The fan (not shown) optionally can be arranged in the analyzer 100, to reduce the temperature in the analyzer 100.In certain embodiments, humidity control system can comprise and is arranged in analyzer Peltier thermoelectric heater and/or cooler.
In certain embodiments, use the recognition system that comprises one or more identifiers, recognition system is associated with one or more assembly or the materials relevant with box and/or analyzer.Following described in more detail, " identifier " itself can use about the information of the assembly that comprises identifier (namely, for example utilize carrying or the inclusion information of information carrying, storage, generation or conveying device (for example RF identification (RFID) label or bar code)) " coding ", " identifier " itself also can be about the information coding of assembly, but only be associated with database or the information in the database on the computer-readable medium (for example, about user's information and/or about the information of sample to be analyzed) that for example can comprise on computers.In rear a kind of example, the detection of this identifier can trigger from database retrieval and use related information.
Use not necessarily will be used a complete set of information coding about assembly about the identifier of the information " coding " of assembly.For example, in certain embodiments, identifier can be with the information of the unique identification that only is enough to realize box (for example, about sequence number, part number etc.) coding, (for example type, use are (for example and about the additional information of box, the type of chemical examination), ownership, orientation, position, connectivity, content etc.) can remote storage, and only be associated with identifier.
Identity, location or orientation about box about " information " of box, material or assembly etc. or with box, material or assembly etc. " information that is associated ", the material of the content of box or assembly or identity, location or orientation, the information of material or assembly, and can additionally comprise character, state or composition about box, material, the information of assembly or content.Can comprise identification box, material or assembly or its content about " information " of box, material or assembly or its content or with information that box, material or assembly or its content " are associated " and with box, material or assembly or its content and other information that distinguishes.For example, about box, " information " of material or assembly or its content or and box, the information that material or assembly or its content " are associated " can refer to represent box, what the type of material or assembly or its content or they are, where they be placed on or where should be placed on, how they are set or how they should be set, box, the function of material or assembly or its content or purpose, box, how material or assembly or its content are connected with other assemblies of system, lot number, origin, calibration information, date of expiry, the destination, box, the manufacturer of material or assembly or its content or ownership, the information of the type of the analysis that will carry out in the box/chemical examination, about whether using/information of analysis box, etc.
In one group of embodiment, identifier is associated with box and/or analyzer described here.Usually, as used herein, term " identifier " expression can provide about box and/or analyzer (information (for example, the one or more information that comprises identity, orientation or the location/position of box and/or analyzer or its assembly) project (identifier is associated with box and/or analyzer by this information or is installed in wherein), the project that perhaps can be identified or detect, and identification or detection event are associated with the information of the box that is associated about identifier and/or analyzer.The non-limiting example of operable identifier especially comprises RF identification (RFID) label, bar code, sequence number, color label, fluorescence or optical tag (for example, using quantum dot), chemical compound, RF tag, magnetic labels in the environment of the present invention.
In one embodiment, schematically show such as Figure 16, analyzer 100 comprises the identification reader 60 that is arranged in the shell, and identification reader 60 is configured to read the information about box 20.Any suitable identification reader all can be used for from the identifier reading information.The non-limiting example of identification reader especially comprises RFID reader, bar code scanner, chemical detector, camera, rf detector, magnetic field or electric field detector.The suitable type of the method that detects/read and identification detector depends on the unique identifier of use, and can comprise for example optical imagery, fluorescence excitation and detection, mass spectral analysis, nuclear magnetic resonance, sequencing, hydridization, electrophoresis, spectral technique, microtechnic etc.In certain embodiments, the identification reader can be installed or embedded in advance specific position (for example, at box and/or above the analyzer or wherein).
In one embodiment, identification reader 60 is the RFID readers that are configured to read the RFID identifier that is associated with box 20.For example, schematically show such as Fig. 2, in one embodiment, analyzer 100 comprises RFID module and the antenna that is configured to from box 20 reading informations that insert analyzer 100.In another embodiment, identification reader 60 is the barcode readers that are configured to read the bar code that is associated with box 20.In case box 20 is inserted analyzer 100, identification reader 60 just can be from box 20 reading informations.Identifier on the box can comprise the information of one or more types, for example the type of box type, the analysis/chemical examination that will carry out, lot number, the information that whether is used/analyzes about box and other information described here.Reader 60 also can be configured to read the information that provides by one group of box, for example in the packing box of box, such as but not limited to the distinctive any additional information of calibration information, date of expiry and this batch.Can optionally to the information of user's Identification display, be performed with the type of for example confirming correct box and/or chemical examination.
In some cases, can will identify reader and control system integration via communication path.Communicating by letter between identification reader and the control system can occur or can pass through wireless way for transmitting along the entity circuit network.In one embodiment, when the indication box is suitably connected or is inserted the analyzer of particular type, control system can be programmed for the special identifier of identification (identifier of the box that for example, is associated with information about box type, manufacturer, the chemical examination that will carry out etc.).
In one embodiment, what comprise in the identifier of box and the database is associated about system or the box predetermined or programming information for the use of specific purpose, user or product, perhaps is associated with special reaction condition, sample type, reagent, user etc.If detect wrong coupling, perhaps identifier is invalid, just can stop processing, perhaps so that system can not operate, until notified the user, perhaps when the user confirms.
In certain embodiments, for example can be stored in the computer storage or be stored on the computer-readable medium from identifier or the information that is associated with identifier, be used for later reference and record keeps.For example, some control system can adopt from identifier or the information that is associated with identifier, with the duration that is identified in type, date, time and the use of having used which assembly (for example, box) or box in the particular analysis, condition of use etc.For example can determine whether to remove or one or more assemblies of replacement analysis device with these information.Optionally, control system or any other suitable system can produce report according to the information of collecting, comprise that by the information of identifier coding or the information that is associated with identifier it can be used for providing the evidence that meets the adjustment standard or the proof of quality control.
For example can be used for also determining that about the information of identifier coding or the information that is associated with identifier the assembly (for example, box) that is associated with identifier is real or personation.In certain embodiments, defining the personation assembly causes system to be stopped work.In one example, identifier can comprise unique identity code.In this example, if detect uncorrelated or unmatched identity code (perhaps not having identity code), process control software or analyzer can the permission system not start (for example, can make system's anergy).
In certain embodiments, carry out the consumer's of biology, chemistry or drug-treated identity from the information of identifier acquisition or the Information Availability that is associated with identifier in the identity that proves the consumer that box and/or analyzer are sold to or for it.In some cases, the information that obtains from identifier or the information that is associated with identifier are used as collecting the part of the processing of data, are used for the trouble hunting of system.Especially identifier also can comprise for example batch job history, assembling processing and instrumentation diagram (P and ID), the historical such information of trouble hunting, and is perhaps associated with it.In some cases, the trouble hunting of system can be finished via remote access, perhaps comprises the use of diagnostic software.
In one embodiment, analyzer 100 comprises user interface 200, user interface 200 can be arranged in the shell 101 and dispose to be used for the user to sample analysis device 100 input messages.In one embodiment, user interface 200 is touch-screens, and it is shown in Fig. 1 and Figure 16 to Figure 21.
To shown in Figure 21, touch-screen can guide the user to the operation of analyzer 100 such as Figure 16, provides text and/or graphics command to be used for the use of analyzer 100.Figure 17 is illustrated in an example that is used for the figure of touch screen user interface 200 when beginning is processed in sample analysis.Figure 18 illustrates the example with the figure of the touch screen user interface 200 of box 20 insertion analyzers 100 for the guiding user.Figure 19 illustrates the example with the figure of the touch screen user interface 200 of patient's name or other patient identifications source/number input analyzer 100 for the guiding user.Should be appreciated that can be with inputting touch screen user interface such as the such patient information of name, birthday and/or patient's id number, with the identification patient.An example that is used for the figure of touch screen user interface 200 when Figure 20 is illustrated in analyzing samples.As shown in the figure, touch-screen can be indicated amount remaining time of finishing sample analysis.At last, Figure 21 illustrates an example of the figure of the touch screen user interface 200 that shows the sample analysis result for name or other identifying informations together with patient.
In another embodiment, can pass through the different modes configuration user interface, for example by LCD display and single button scroll through menus.In another embodiment, user interface can comprise the start button of startup analysis device simply.In other embodiments, the user interface from independent self-contained unit (for example smart phone or mobile computer) can be used for and the analyzer interface.
Can process and analyze the sample that is placed in the analyzer with above-mentioned analyzer 100 by variety of way.In a particular embodiment, in case be configured to indicate boxes 20 by the analyzer 301 of correctly packing into the mechanical component 121 of cartridge interface the information that identity reader 60 just reads and identification is associated with box 20.The data that analyzer 100 can be configured to store in this information and control system compare, and have calibration information for this specific sample to guarantee it.Do not have at analyzer in the situation of correct calibration information, analyzer can be exported request to the user, to upload the specific information that needs.Analyzer can be configured to check the date of expiry information that is associated with box in addition, if passed through the date of expiry, just cancellation is analyzed.
In one embodiment, in case determined can analysis box 20 for analyzer 100, just can will be configured to contact box 20 such as vacuum manifold 48 such Fluid Flow in A sources, to guarantee vacuum ports 219 and blow vent 215 hermetically sealing on every side.In one embodiment, optical system 80 can be carried out initial measurement, to obtain reference count.Can by the light source 82 that starts and close, 86 both obtain these reference counts.
In order to begin the movement of sample, can start vacuum system 40, the pressure that vacuum system 40 can change rapidly in the passage 206,207 (for example, reduces to approximately-30kPa).This minimizing of pressure can be advanced to sample and also pass through each measured zone 209A-209D(in the passage 206 referring to Fig. 8 in the passage).After sample arrived final measured zone 209D, sample can continue to flow into liquid containing zone 217.
In a particular embodiment, microfluid sample analysis device 100 is used for measuring the level of blood sample prostate specific antigen (PSA).In this embodiment, can use four measuring zone 209A-209D analyzing samples.For example, in the first measured zone, can conduit wall be blocked with blocking protein (for example bovine serum albumin(BSA)), so not have or almost do not have protein adherence in the blood sample at the wall (except some the nonspecific combination that can wash off of possibility) of measured zone 209.This first measured zone can be served as negative control.
In the second measured zone 209, can apply with predetermined a large amount of prostate specific antigens (PSA) wall of passage 206, to serve as height or positive control.When blood sample passes through the second measured zone 209, there is not or almost do not have PSA protein to be combined with conduit wall in the blood.Golden pairing signal antibody in the sample can from the inside dissolving of fluid connector pipeline 222, also can flow from any other suitable position.These antibody not necessarily PSA in sample are combined, and therefore they can be combined by the PSA on conduit wall, to serve as height or positive control.
In the 3rd measured zone 209, can apply with predetermined a small amount of PSA the wall of passage 206, to serve as low control.When blood sample flows through this measured zone 209, there is not PSA protein to be combined with conduit wall in the sample.Golden pairing signal antibody in the sample can also can flow from any other suitable position, and can be combined by the PSA on conduit wall from the inside dissolving (the PSA with sample is not combined) of fluid connector pipeline 222, to serve as low control.
In the 4th measured zone 209, can use capture antibody (a kind of anti-PSA antibody) to apply the wall of passage 206, epi-positions different with golden pairing signal antibody on capture antibody and the PSA protein are combined.When blood sample flowed through the 4th measured zone, the PSA protein in the blood sample can be combined with anti-PSA antibody in the proportional mode of the concentration of these protein in blood.Therefore, in one embodiment, three measured zone 209 in front can be served as control, and four measuring zone 209 in fact can test sample book.In other embodiments, can provide the measured zone of varying number, and analyze and optionally to comprise more than one the in fact measured zone of test sample book.
In some instances, not only can be used for determining the concentration of analyte in the sample from the measurement result in the zone (for example, above-mentioned the 4th measured zone) of analyzing samples, and can be as control.For example, can set up the threshold measurement result at the commitment that amplifies.The measurement result that is higher than this value (perhaps being lower than this value) can indicate the concentration of analyte outside the expected range of chemical examination.Whether this technology during for example can be used for being identified in analysis high dose hook effect has occured, that is, and and when very the analyte of high concentration provides false low scale.
In other embodiments, can provide the measured zone of varying number, and analyze and optionally to comprise more than one the in fact measured zone of test sample book.Additional measured zone can be used for measuring additional analyte, so system can carry out multiple chemical examination simultaneously to single sample.
In a particular embodiment, 10 microliters of blood samples flow through four measuring zone 209 and approximately want 8 minutes.When the pressure in the passage 206 approximately be-can calculate the startup of this analysis during 30kPa.In this time, optical system 80 is measured output optical transmission for each measured zone, and in one embodiment, can approximately per 0.1 second with this transfer of data to control system.Use reference value, can utilize following formula to change these measurement results:
Transmissivity=(l-ld)/(lr-ld) (1)
Wherein:
L=point preset time is by the transmission light intensity of measured zone
When closing, passes through the ld=light source transmission light intensity of measured zone
The lr=referenced strength (that is when, light source starts or when only have air in the passage analyze begin before the transmission light intensity of measured zone)
And
Optical density=-the log(transmissivity) (2)
Therefore, use these formula, the optical density in can computation and measurement zone 209.
As described here, can make the Fluid Flow in A in control box that ins all sorts of ways, comprise pump, vacuum plant, valve and the use of other assemblies of being associated with analyzer.In some cases, also can carry out fluid control by the one or more assemblies in the box at least in part, for example by using the valve that arranges in the box, perhaps by the special fluid of box and the use of passage configuration.In one group of embodiment, based on the impact of channel geometries and the viscosity of one or more fluids of cassette interior (can be stored), can realize the control of Fluid Flow in A at least in part.
A kind of method is included in low viscous flow scapus and high-viscosity fluid post is flowed.In one embodiment, the low viscous flow body flows with the first flow rate in passage, and flow rate is not subjected to the impact of fluid mobile in the mobile constricted zone basically.When high-viscosity fluid flows to when flowing constricted zone from non-constricted zone, the flow rate of fluid reduces basically, because in some systems, and the high-viscosity fluid impact that flow rate is subjected to flow in the smallest cross-sectional area (for example, flow constricted zone) of system.Cause like this low viscous flow body to flow to compare the second slower flow rate of original flow rate, for example flow with the identical speed of speed that in the constricted zone that flows, flows with high-viscosity fluid.
For example, a kind of method of controlling Fluid Flow in A can relate to makes first fluid partly flow to the second channel part from first passage in microfluid system, the cross-sectional area that the fluid path that wherein partly limits by first passage is compared the fluid path that partly limits by second channel has larger cross-sectional area, and second fluid flows in the third channel part of microfluid system, the third channel part is communicated with first passage part and second channel segment fluid flow, wherein the viscosity of first fluid is different from the viscosity of second fluid, and wherein first fluid and second fluid can not compress in fact.In the situation that does not stop first fluid or second fluid, than not making first fluid partly flow to the second channel part from first passage, partly flow to the result of second channel part as first fluid from first passage, the volume flow rate of first fluid and second fluid can descend one and is at least 3, is at least 10, is at least 20, is at least 30, is at least 40 or be at least 50 the factor in microfluid system.When first fluid and second fluid flow with lower flow rate, relate to the chemistry of composition of first fluid or second fluid and/or the first measured zone generation that biology interacts and can be communicated with the channel part fluid.
Therefore, be positioned at ad-hoc location by microfluid system being designed to mobile constricted zone, and by selecting suitable fluid viscosity, can make the fluid acceleration or deceleration by the diverse location in system, and not need to use valve and/or do not need external control.In addition, length that can the selector channel part is retained in cycle specific region regular hour of system to allow fluid.For carrying out chemistry and/or biological assay and wherein other very important application of timing of reagent, such system is particularly useful.
Figure 16 illustrates according to an embodiment, and control system 305(is referring to Figure 13) block diagram 300 that how in operation, is associated from various different assemblies.Can be accomplished in several ways control system described here, for example by specialized hardware or firmware, utilize and use the processor of microcode or software programming to carry out above-mentioned functions or aforesaid any appropriate combination.Control system can be controlled one or more operations (for example, being used for biological, biochemistry or chemical reaction) of single analysis, perhaps one or more operations of a plurality of (independent or interconnection) analysis.Shown in Figure 13 is exemplary, control system 305 can be arranged in the shell 101 of analyzer, and control system 305 can be configured to communicate by letter with identifying reader 60, user interface 200, Fluid Flow in A source 40, optical system 80 and/or humidity control system, with the sample in the analysis box.
In one embodiment, control system comprises at least two processors, comprises control and monitoring directly and the real-time processor of whole subsystems of cartridge interface.In one embodiment, this processor with the specific time interval (for example, per 0.1 second), with the second high-grade processor communication, and the operation of guide analyzer (for example, when determine startup analysis sample and explanation result), the second high-grade processor is by user interface and/or communication subsystem (as described below) and telex network.In one embodiment, the communication between these two processors occurs by serial communication bus.Should be appreciated that in another embodiment analyzer can include only a processor, perhaps two above processors the invention is not restricted to this.
In one embodiment, analyzer can with Peripheral Interface, and for example can comprise be used to the port that connects one or more external communications units.For example can finish PERCOM peripheral communication via usb communication.For example, exemplary as Figure 16 shown in, analyzer can be to USB printer 400 or the result who analyzes to computer 402 output samples.Additionally, can output to by the data flow that real-time processor produces computer or usb memory stick 404.In certain embodiments, computer can also connect direct control analysis device by USB.In addition, the invention is not restricted to this, the communication of other types is selected also to be fine.For example, can be by Ethernet, bluetooth and/or the WI-FI communication 406 of processor Establishment and analysis device.
Can utilize computer implemented control system to realize computational methods described here, step, emulation, algorithm, system and system element, for example the various embodiment of computer implemented system described below.Method described here, step, system and system element are not limited to any specific computer system described here with regard to their realization, also can use a lot of other different machines.
Computer implemented control system can be the part of sample analysis device, perhaps in operation, couple explicitly with the sample analysis device, and, in certain embodiments, computer implemented control system is disposed and/or is programmed for the operating parameter of control and adjusting sample analysis device, and the analysis and calculation value, as mentioned above.In certain embodiments, computer implemented control system can the sending and receiving reference signal, setting and/or the operating parameter of control sample analysis device, and arranges alternatively and/or control the operating parameter of other system equipment.In other embodiments, computer implemented control system can be separated with the sample analysis device and/or about the long-range setting of sample analysis device, and can be configured to via indirect and/or portable device, for example via portable electronic data storage device structure (for example disk), perhaps via the communication on the computer network (for example internet or LAN), from one or more long-range sample analysis device equipment receiving datas.
Computer implemented control system can comprise some known assemblies and circuit, comprise processing unit (being processor), accumulator system, input/output unit and interface (for example interconnection mechanism) and other assemblies, for example delivery circuit (for example, one or more buses), Audio and Video data I/O (I/O) subsystem, specialized hardware and other assemblies and circuit, following described in more detail.In addition, computer system can be multiprocessor computer system, perhaps can comprise a plurality of computers that connect by computer network.
Computer implemented control system can comprise processor, commercial processor for example, x86, Celeron and the Pentium processor series that for example can obtain from Intel wherein a kind of, similarly install from AMD and Cyrix, the 680X0 series microprocessor that can obtain from Motorola, and from the PowerPC of IBM.A lot of other processors also can be used, and computer system is not limited to par-ticular processor.
Processor is carried out the program that is called operating system usually, WindowsNT, Windows 95 or 98, UNIX, Linux, DOS, VMS, MacOS and OS8 are the examples of operating system, and it is controlled the execution of other computer programs and scheduling, debugging, I/O control, accounting, editor, memory distribution, data management and storage management, Control on Communication and related service are provided.The computer platform that the application program that the common restriction of processor and operating system is write with high-level design languages is used for.Computer implemented control system is not limited to specific computer platform.
Computer implemented control system can comprise accumulator system, the nonvolatile recording medium that accumulator system generally includes computer-readable and can write, and disk, CD, flash memory and tape are its examples.Such recording medium can be movably, and for example floppy disk, read/write CD or memory stick also can be fixed, for example hard disk drive.
Such recording medium is usually with the binary form form of the explanation of 1 and 0 sequence (that is, with) storage signal.Dish (for example disk or CD) has a plurality of tracks, and the above can store these signals, usually with binary form, that is, and the form of the sequence explanation with 1 and 0.These signals can limit software program (for example application program) or the application program information to be processed that microprocessor will be carried out.
The accumulator system of computer implemented control system also can comprise the integrated circuit memory element, normally volatile random access memory, for example dynamic random access memory (DRAM) or static memory (SRAM).Usually, in operation, processor makes program and data read the integrated circuit memory element from nonvolatile recording medium, compares nonvolatile recording medium, and the integrated circuit memory element allows processor to programmed instruction and faster access of data usually.
Processor is handled data in the integrated circuit memory element according to programmed instruction usually, finish process after with the data Replica of manipulation to nonvolatile recording medium.Known various mechanism is used for the data mobile between managing non-volatile recording medium and the integrated circuit memory element, and realization is not limited to this about the computer implemented control system of said method, step, system and the system element of Figure 16.Computer implemented control system is not limited to the specific memory system.
At least a portion of above-mentioned sort memory system can be used for storing one or more data structures (for example, look-up table) or aforesaid equation.For example, at least a portion nonvolatile recording medium can be stored at least a portion database that comprises one or more this data structures.This database can be any of various types of data storehouse, for example, comprises the file system of one or more flat file data structures, wherein with Organization of Data in the data cell of separating with separator; Relational database, wherein with Organization of Data in the data cell with form stores; Object-oriented database, wherein with Organization of Data in the data cell as object storage; The database of other types or their any combination.
Computer implemented control system can comprise Audio and Video data I/O subsystem.The audio-frequency unit of subsystem can comprise modulus (A/D) converter, and it receives analog audio information and is converted into digital information.Can use known compressibility compressed digital information, be used for storing at hard disk, use at other times.The exemplary video part of I/O subsystem can comprise video image compression device/decompressor, and a lot of video image compression device/decompressors are known in the art.These compresser/decompresser are converted to the digital information of compression with analogue video signal, and vice versa.The digital information of compression can be stored on the hard disk, is used for using later on.
Computer implemented control system can comprise one or more output devices.Exemplary output device comprises cathode ray tube (CRT) display, liquid crystal display (LCD) and other video output devices, printer, communicator (for example modem or network interface), storage device (for example disk or tape) and audio output device (for example loudspeaker).
Computer implemented control system also can comprise one or more input units.Exemplary input unit comprises keyboard, key plate, trace ball, mouse, pen and board, communicator (for example as above above-mentioned) and data input device (for example Voice ﹠ Video acquisition equipment and sensor).Computer implemented control system is not limited to the specific device that inputs or outputs described here.
One or more of any type that should be appreciated that computer implemented control system can be used for realizing various embodiment described here.The solution of the present invention can realize by software, hardware or firmware or their any combination.Computer implemented control system can comprise the specialized hardware of special programming, for example special IC (ASIC).These specialized hardwares can be configured to as the part of above-mentioned computer implemented control system or as stand-alone assembly, realize the one or more of said method, step, emulation, algorithm, system and system element.
Computer implemented control system and assembly thereof can use any programming of various suitable computer programming languages.These language can comprise programming language, for example C, Pascal, Fortran and BASIC, object-oriented language, for example C++, Java and Eiffel, and other language, for example script or assembler language.
Use any of various suitable programming languages, can implementation method, step, emulation, algorithm, system and system element, comprise programming language, OO design language, other language and the combination thereof that can carry out by this computer system.These methods, step, emulation, algorithm, system and system element can be embodied as the separate modular of computer program, can single realization be independent computer program also.Can carry out these modules and program at independent computer.
These methods, step, emulation, algorithm, system and system element can be individually, perhaps be embodied as in combination computer program, computer program visibly is embodied as the computer-readable signal on the computer-readable medium, for example nonvolatile recording medium, integrated circuit memory element or their combination.For each such method, step, emulation, algorithm, system or system element, this computer program can be included in the computer-readable signal of visibly implementing on the computer-readable medium that limits instruction, for example as the part of one or more programs, the result who namely carries out as computer, the command calculations machine carries out method, step, emulation, algorithm, system or system element.
Should be appreciated that by one or more above-mentioned features and can form various embodiment.Can in any suitable combination, adopt such scheme and feature, therefore the invention is not restricted to this.Should be appreciated that in addition accompanying drawing illustrates various assemblies and the parts that may be incorporated among the various embodiment.For simplicity, some accompanying drawings can illustrate an above selective part or assembly.But, the invention is not restricted to disclosed specific embodiment in the accompanying drawing.Will be appreciated that the embodiment that can include only a part of assembly shown in any one accompanying drawing is contained in the present invention, and/or also can contain the embodiment of the assembly shown in a plurality of different accompanying drawings of combination.
Example
Following example is for some feature of the present invention is shown, rather than four corner of the present invention is described.
Example 1
This example is described the use of box and analyzer, with by the electroless coating mode with deposition of silver with gold grain that sample is associated on, chemically examine to detect the PSA in the sample.Figure 22 comprises the schematic diagram of the microfluid system 500 of the box that uses in this example.This box has the shape similar to box shown in Figure 3 20.The denomination of invention that the microfluid system that uses in this example was submitted on November 20th, 2004 is the international patent application No.WO2005/066613(international patent application no No.PCT/US2004/043585 of " assay device and method ") in carried out general description.
Microfluid system comprises measured zone 510A-510D, refuse retaining zone 512 and exports 514.Measured zone comprises microfluidic channel, and 50 microns dark, and 120 microns wide, total length 175mm.Microfluid system comprises that microfluidic channel 516 and channel branch 518 and 520(have respectively entrance 519 and 521 in addition ).Channel branch 518 and 520 be 350 microns dark and 500 microns wide.Passage 516 is formed by subchannel 515, subchannel 515 be 350 microns dark and 500 microns wide, be arranged on the both sides of box, the through hole 517 by 500 microns of diameters connects.Although Figure 22 illustrates one-sided at box of reagent storage, in other embodiments, can be with the both sides of reagent storage at box.The total length of passage 516 is 390mm, and branch 518 and 520 each long 360mm.Before channel seal, anti-PSA antibody is attached to the surface of microfluid system in the fragment of measured zone 510.
Before using first, with the liquid reagent of storing in the box microfluid system of packing into.Use pipette with one group of 7 column scrubber 523-529(water or buffer, each about 2 microlitre) subchannel 515 of the passage 516 that uses through hole of packing into.By air column each column scrubber is separated.Use pipette, the fluid 528 that will comprise silver salt solution by port 519 branched bottom of packing into.The fluid 530 that will comprise reducing solution by port 521 branched bottom 520 of packing into.By air column with each liquid shown in Figure 9 and other fluid separation applications.By the adhesive belt that can easily remove or wear out port 514,519,521,536,539 and 540 is sealed.Therefore, before using first with liquid storage in microfluid system.
When using first, tear the belt that covers port 514,519,521,536,539 and 540 opening by the user, with these port depressurizations.To comprise with the anti-PSA antibody of freeze-drying of gold colloid mark and the pipeline 544 that wherein added 10 microliters of blood samples (522) and be connected to port 539 and 540.Pipeline is the part with fluid connector of shape shown in Figure 3 and configuration.Produced like this measured zone 510 and be connected with fluid between the passage 516, and before using first, they mutually do not connect and do not have fluid to be communicated with.
To comprise that the box of microfluid system 500 inserts the opening (for example Figure 10, Figure 12 and shown in Figure 17) of analyzer.The shell of analyzer comprise be arranged in the shell be configured to box on the arm of cam.Arm extends in the opening in the shell at least in part, therefore when box insertion opening, arm is pushed the second place from opening, so that box enters opening.In case arm engages with the interior cam surface of box, box just is set up and is retained in the shell of analyzer, and the biasing of spring prevents that box from skidding off analyzer.Analyzer is by the insertion of position sensors sense box.
Be arranged on identification reader (RFID reader) in the analyzer shell and be used for reading RFID label on the box, it comprises a batch identifying information.The batch information that analyzer stores in the matching analysis device with this identifier (for example, the date of expiry of calibration information, box, box are the types of the analysis that will carry out in new proof and the box/chemical examination).The user is prompted to use the touch-screen will be about (therefrom obtaining sample) patient's input information analyzer.The user examines after the information about box, and control system begins to analyze.
Control system comprises the programmed instruction of analyzing.In order to begin to analyze, send signal to the electronic installation of control vacuum system, vacuum system is the part of analyzer and is used for providing Fluid Flow in A.To press to the box surface with the manifold of O shape ring by solenoid.A port on the manifold (by O shape ring) is sealed in the port 536 of the microfluid system of box.This port on the manifold is connected to simple solenoid valve (SMC V124A-6G-M5, not shown) to atmosphere opening by pipeline.Independent vacuum ports on the manifold (by O shape ring) is sealed in the port 514 of the microfluid system of box.With approximately-vacuum application of 30kPa is in port 514.In whole analysis, comprise that the passage of the measured zone 510 that is arranged between port 540 and 514 has the non-zero pressure drop of substantial constant, approximately-30kPa.Sample 522 flows into each measured zone 510A-510D along the direction of arrow 538.When fluid passed through measured zone, the PSA protein in the sample 522 is fixed on the anti-PSA antibody capture on the measured zone wall, and was following described in more detail.Sample is spent about 7-8 minute by measured zone, is hunted down in refuse retaining zone 512 afterwards.
The beginning of analyzing also relates to the control system of fluorescence detector transmitted signal, and it is adjacent with each measured zone 510 that fluorescence detector is set to, to begin detection.Each detector recording that is associated with measured zone is by the transmissivity of the light of the passage of measured zone, as shown in Figure 10 shown in the curve map 600.When sample passes through each measured zone, produce peak 610A-610D.The peak of detectors measure (and paddy) is the signal (perhaps being converted to signal) that sends to control system, and control system compares the signal of measuring and the reference signal or the value that are programmed in advance control system.Control system comprises in advance the instruction group of programming, and being used at least in part providing feedback based on the comparative result of signal/value to microfluid system.
In the first measured zone 510-A of the device 500 of Figure 22, before using first (for example, before will install sealing), can be with blocking the conduit wall obstruction of protein (for example bovine serum albumin(BSA)) with this measured zone.There is not or almost do not have protein to be attached at the wall (except some the non-special combination that can wash off of possibility) of measured zone 510-A in the blood sample.This first measured zone is served as negative control.
In the second measured zone 510-B, before using first (for example, before will installing sealing), can apply with predetermined a large amount of prostate specific antigens (PSA) conduit wall of this measured zone, to serve as height or positive control.When blood sample passes through the second measured zone 510-B, there is not or almost do not have PSA protein to be combined with conduit wall in the blood.Golden pairing signal antibody in the sample not necessarily PSA in sample is combined, and therefore they can be combined by the PSA on conduit wall, to serve as height or positive control.
In the 3rd measured zone 510-C, before using first (for example, before will installing sealing), can apply with predetermined a small amount of PSA the conduit wall of this measured zone, to serve as low control.When blood sample flows through this measured zone, there is not or almost do not have PSA protein to be combined with conduit wall in the sample.Golden pairing signal antibody in the sample can be combined by the PSA on conduit wall, to serve as low control.
In the 4th measured zone 510-D, apply the conduit wall of this measured zone with capture antibody (a kind of anti-PSA antibody), epi-positions different with golden pairing signal antibody on capture antibody and the PSA protein are combined.(for example, will install seal before) applies wall before using first.In use when blood sample flowed through the 4th measured zone, the PSA protein in the blood sample can be combined with anti-PSA antibody by the proportional mode of the concentration of these protein in blood.Because sample comprises PSA, comprise that also the gold that is connected to PSA matches anti-PSA antibody, so the PSA that catches on the measured zone wall forms the sandwich immunoassay compound.
Washing lotion 523-529 follows sample and flows to refuse retaining zone 512 by measured zone 510 along the direction of arrow 538.When washing lotion was passed through measured zone, they washed off remaining not in conjunction with the sample composition.Each column scrubber cleans the passage of measured zone, constantly provides more completely to clean.Last washing lotion 529(water) wash the salt (for example, chloride, phosphate, azide) of understanding with the silver salt reaction off.
Shown in the curve map as shown in Figure 23, when washing lotion flows through measured zone, each the detectors measure peak that is associated with measured zone and the pattern 620 of paddy.Paddy is corresponding to column scrubber (column scrubber is clear liquid, and therefore maximum light transmission is provided).Peak between each post represents the air between each post of clear liquid.Because chemical examination comprises 7 column scrubbers, so 7 paddy and 7 peaks are arranged in curve map 600.First paddy 622 is general different dark with other paddy 624, this be because the first column scrubber often seizure stay blood cell in the passage, thereby not exclusively limpid.
Because there is not column scrubber to follow, therefore last air peak 628 is longer than the peak of front.When detector detects the length of this air peak, one or more signals are sent to control system, control system compares the time span at this peak with preset reference signal or input value with length-specific.If the time span at the peak of measuring is than the reference signal long enough, then control system is to the electronic installation transmitted signal of control gas valve 536, to start valve and to begin fluid 528 and 530 mix.(note, the signal of air peak 628 can with following any the signal combination of indication: the 1) intensity at peak; 2) as the position at this peak of the function of time; And/or 3) one or more signals are pass by at the one group peak 620 of indication with certain strength.In this way, control system distinguishes other peaks of air peak 628 and longer duration the peak 610 of sample (for example from), for example uses the pattern of signal.）
In order to begin to mix, will close by the solenoid that manifold connects blow vent 536.Since vacuum plant maintenance work, and do not have air to enter by gas valve 536, so air is opened by port 519 and 521(port 519 and 521) access to plant.Impel like this two fluids 528 and 530 in two memory channels of gas valve 536 upstreams basically to move to outlet 514 simultaneously.These reagent mix in the crosspoint of passage, form to have about 1x10 -3The amplification reagent of the viscosity of Pas (reacting silver-colored solution).Fluid 528 approximately is 1:1 with the volume ratio of fluid 530.Amplify reagent and pass through continuously the downstream memory channel, pass through pipeline 544, pass through measured zone 510, then arrive refuse retaining zone 512.Through the time quantum (12 seconds) of setting, analyzer reopens gas valve, so that Air Flow is not blow vent by gas valve 536().Like this some reagent are waited behind, in the upstream memory channel 518 and 520 on device.So also cause single Hybrid amplifier reagent post.Gas valve is closed the amplification post that caused about 50 μ L in 12 seconds.(except simple timing, the another kind of mode that the triggering gas valve reopens is to detect it when amplifying when reagent enters measured zone first.）
Because the stable of Hybrid amplifier reagent only continues a few minutes (usually being less than 10 minutes), so be less than 1 minute mixing before in measured zone 510, using.Amplifying reagent is clear liquid, and therefore when it entered measured zone, optical density was in its minimum of a value.When amplifying reagent through measured zone, deposition of silver increases the size of colloid on the gold grain of catching, signal is amplified.(as mentioned above, in the thermometrically zone, gold grain appears in the low and high positive control measured zone, and, arrive the degree that occurs PSA in the sample.) then silver can be deposited on the silver that deposited above, stay increasing deposition of silver in measured zone.At last, the silver of deposition reduces the transmissivity by the light of measured zone.The silver amount of the minimizing of transmitted light and deposition is proportional, and relevant with the gold size scale of construction of catching on the conduit wall.In not having the measured zone of deposition of silver (for example, negative control, the perhaps test zone when sample does not comprise target protein (for example PSA)), optical density does not increase (perhaps minimum increase).The measured zone of remarkable deposition of silver is being arranged, and the slope of the pattern of the optical density of increase and terminal level can be very high.The analyzer monitoring pattern of this optical density in the test zone during amplifying is to determine the concentration of analyte in the sample.In a kind of form of test, in first 3 minutes that amplify, monitor pattern.Optical density as the function of time in each measured zone is recorded, and is shown in Figure 10 for curve 640,644,642 and 646.These curves correspond respectively to the signal that produces among measured zone 510-A, 510-B, 510-C and the 510-D.
After 3 minutes amplification, analyzer stops test.More optical measurement results are not recorded, and manifold breaks away from from device.Test result is presented on the analyzer screen and sends any output of printer, computer or user selection to.The user can remove device and abandon from analyzer.The whole reagent that use in sample and the chemical examination all are retained in the device.Analyzer is ready to another time test.
Should be noted that the control of the flow rate of fluid is very important in passage 516 and the measured zone 510 when Fluid Flow in A passes through system.Because the less cross-sectional area of measured zone, this is the bottleneck of flow rate total in the control system.When measured zone comprised liquid, the linear flow rate of fluid approximately was 0.5mm/s in the passage 516.The fluid that flows into main channels 516 from branched bottom 518 and 520 under this speed not necessarily reproducibility ground mix faster than another because fluid may flow, cause the different piece of fluid 528 and 530 to be mixed.On the other hand, when measured zone comprised air, the linear flow rate of fluid approximately was 15mm/s in passage 516 and branched bottom 518 and 520.Under this higher flow rate, branched bottom 518 and flow rate identical and reproducible (when gas valve 536 is closed) in 520 produce reproducible mixing.For this reason, the valve of connectivity port 536 is not closed, until fluid 542 arrives the refuse retaining zone by measured zone.As mentioned above, utilize fluorescence detector to determine when fluid 542 withdraws from measured zone, thereby in conjunction with the transmissivity of reponse system measurement by the light of a part of measured zone 510.
Microfluid system shown in Figure 22 is designed so that the volume of the passage between gas valve 536 and the measured zone 510 is greater than the intended volume of the silver-colored solution of the activation that mixes (that is, advancing to fluid 528 in the passage 516 and 530 built-up section) when gas valve 536 is closed.Guaranteed that so basically all mixing all occur under the higher linear flow rate and (because do not have liquid this moment in measured zone 510, only have air), and the solution that occurs in activation arrives before the measured zone.This configuration helps lend some impetus to reproducible and mixing that be equal to.For the chemical examination described in this example, the lasting a few minutes (for example, 2 to 10 minutes) of flowing of keeping the silver-colored mixture that activates in the measured zone are very important.
This example illustrates by using the analyzer of Fluid Flow in A in the control box, and regulates Fluid Flow in A by using from the feedback of the signal of one or more measurements, can carry out the analysis of sample in the microfluid system of box.
Although described and illustrated some embodiment of the present invention here, but those skilled in the art are easy to conceive for carrying out function and/or obtain the result and/or various other devices and/or the structure of one or more advantages described here, and each such variation and/or revise to be considered and fall within the scope of the present invention.

Claims (92)

1. microfluid sample analysis device comprises:
Shell;
Opening, be arranged in described shell and be configured to hold box, described box has at least one passage that fluid sample is wherein arranged and at least one microfluidic channel and has cross sectional dimensions less than 1mm, wherein, described shell comprise be configured to described box on the matable assembly interface, to detect the assembly of the described box in the described shell;
Be arranged on the control pressurer system in the described shell, described at least one passage that described control pressurer system is configured in the described box is exerted pressure, with mobile described sample by described at least one passage; And
Be arranged on the optical system in the described shell, described optical system comprise a plurality of light sources and with the separated a plurality of detectors of described a plurality of light sources, wherein said light source is configured to make when described box inserts described sample analysis device light to pass through described box, and wherein described detector is set to relative to described light source to detect the light quantity by described box;
Wherein, described a plurality of light source comprises the first light source and the secondary light source adjacent with described the first light source at least, wherein said the first light source is configured to make light by the first measured zone of described box, and described secondary light source is configured to make light by the second described box, adjacent with described the first measured zone measured zone.
2. method of analyzing the microfluid sample, described method comprises step:
The microfluid sample analysis that comprises shell device is provided, in the described shell opening is arranged, wherein include box in the opening in shell, the assembly of wherein said box or described box comprises the passage that at least one wherein has fluid sample;
By the identification reader identification that arranges in the described shell information about described box;
Process user is input to the information of the user interface in the described shell that is arranged on described sample analysis device;
Exert pressure to described at least one passage in the described box by the control pressurer system that is arranged in the described shell, pass through described at least one passage with mobile described sample;
Start optical system, described optical system makes from first measured zone of the light that is arranged on the first light source in the described shell by described box;
By being arranged on the first detector described optical system, relative with described the first light source in the described shell, detect the output optical transmission by described first measured zone of described box; And
By being arranged on the control system in the described shell, analyze the described sample in the described box, described control system is communicated by letter with described identification reader, described user interface, described control pressurer system, described optical system and described humidity control system.
3. such as each described microfluid sample analysis device in the aforementioned claim, comprise the identification reader that is arranged in the described shell and is configured to read the information that is associated with described box.
4. such as each described microfluid sample analysis device in the aforementioned claim, comprise the humidity control system that is arranged in the described shell, described humidity control system comprises the heater that is configured to heat described box.
5. each described microfluid sample analysis device as in the aforementioned claim comprises being arranged in the described shell and being configured to make the user to the user interface of described sample analysis device input message.
6. such as each described microfluid sample analysis device in the aforementioned claim, wherein said detector is conditioned and is arranged as the output optical transmission that detects by the measured zone of described box.
7. such as each described microfluid sample analysis device in the aforementioned claim, close described the first light source unless wherein said light source is configured such that, otherwise do not start described secondary light source.
8. such as each described microfluid sample analysis device in the aforementioned claim, comprise control system, described control system is configured to communicate by letter with control pressurer system, optical system, identification reader, user interface and/or humidity control system, to analyze the described sample in the described box.
9. such as each described microfluid sample analysis device in the aforementioned claim, wherein said the first light source is launched the light of the first wavelength, the light of described secondary light source emission second wave length, and wherein said the first wavelength is identical with described second wave length.
10. such as each described microfluid sample analysis device in the aforementioned claim, wherein said the first light source is launched the light of the first wavelength, the light of described secondary light source emission second wave length, and wherein said the first wavelength is different from described second wave length.
11. as each described microfluid sample analysis device in the aforementioned claim, the assembly that is configured on the wherein said shell with described cartridge interface is the arm that spring is housed.
12. such as each described microfluid sample analysis device in the aforementioned claim, wherein said identification reader is the RFID reader that is configured to read the RFID tag that is associated with described box.
13. such as each described microfluid sample analysis device in the aforementioned claim, wherein said identification reader is the barcode reader that is configured to read the bar code that is associated with described box.
14. such as each described microfluid sample analysis device in the aforementioned claim, wherein said user interface comprises touch-screen.
15. such as each described microfluid sample analysis device in the aforementioned claim, wherein said user interface comprises LCDs.
16. as each described microfluid sample analysis device in the aforementioned claim, further comprise communication system, described communication system is configured to communicate by letter with described control system with will be about the information output of described sample to second unit.
17. such as each described microfluid sample analysis device in the aforementioned claim, wherein said humidity control system also comprises the controller circuitry that is configured to monitor the thermocouple of the temperature in the described shell and is configured to control the temperature in the described shell.
18. such as each described microfluid sample analysis device in the aforementioned claim, wherein said heater is resistance heater.
19. such as each described microfluid sample analysis device in the aforementioned claim, wherein said humidity control system also comprises the cooler that is configured to cool off described box.
20. such as each described microfluid sample analysis device in the aforementioned claim, wherein said cooler is fan.
21. as each described microfluid sample analysis device in the aforementioned claim, wherein said control pressurer system comprises vacuum source, manifold, pressure sensor and valve, wherein said manifold is used for described vacuum source is couple at least one passage of described sample analysis device, described pressure sensor is configured to measure the pressure in the described manifold, and described valve is arranged between described vacuum source and described at least one passage.
22. such as each described microfluid sample analysis device in the aforementioned claim, wherein said control pressurer system comprises membrane pump.
23. such as each described microfluid sample analysis device in the aforementioned claim, wherein said valve is solenoid valve.
24. such as each described microfluid sample analysis device in the aforementioned claim, wherein said the first light source is light emitting diode.
25. such as each described microfluid sample analysis device in the aforementioned claim, wherein said the first light source is photodiode.
26. such as each described microfluid sample analysis device in the aforementioned claim, also comprise the box in the described shell that inserts described analyzer, described box has at least one passage that wherein accommodates sample.
27. such as each described microfluid sample analysis device in the aforementioned claim, the diameter of wherein said at least one passage is between about 50 μ m and about 500 μ m.
28. such as each described microfluid sample analysis device in the aforementioned claim, at least one passage in the wherein said box comprises mutual separated first passage and second channel.
29. as each described microfluid sample analysis device in the aforementioned claim, also comprise removably the fluid connector that couples with described box, wherein said fluid connector comprises and is configured to connect the first passage of described box and the passage of second channel by the fluid mode when described fluid connector removably couples with described box.
30. as each described microfluid sample analysis device in the aforementioned claim, wherein said box comprises and the cam face with the assembly interfaces of described cartridge interface of being configured to that is positioned on the described shell.
31. such as each described microfluid sample analysis device in the aforementioned claim, wherein said a plurality of light sources are configured to once only to start the mode sequence starting of a light source.
32. such as each described microfluid sample analysis device in the aforementioned claim, wherein said a plurality of light sources are configured to start about at least 100 microseconds.
33. as each described method in the aforementioned claim, the humidity control system that comprises being arranged in the described shell of described sample analysis device heats described box.
34. as each described method in the aforementioned claim, wherein, first passage and second channel interconnection that fluid connector does not connect described box by the fluid mode, thereby the formation fluid is communicated with between described first passage and described second channel.
35. as each described method in the aforementioned claim, wherein, before described box uses first, in described first passage and the described second channel at least one comprises the reagent of storage, and described box is sealed described reagent is stored in described box at least one day before using first.
36. such as each described method in the aforementioned claim, wherein, the reagent of described storage is liquid.
37. as each described method in the aforementioned claim, wherein, before described box uses first, in described first passage and the described second channel at least one comprises first fluid reagent and the second fluid reagent that is separated by the 3rd fluid, and described the 3rd fluid all can not mix basically with described first fluid, described second fluid.
38. such as each described method in the aforementioned claim, comprising: before described box uses first, in described fluid connector, comprise fluid sample.
39. as each described method in the aforementioned claim, wherein said identifying information comprises the lot number of identifying described box, calibration information and in the date of expiry at least one.
40. as each described method in the aforementioned claim, described first measured zone of wherein said box comprises bending channel, described bending channel comprises a plurality of fragments, and wherein said the first optical system is set to adjacent with the fragment more than of described bending channel.
41. as each described method in the aforementioned claim, wherein detect and comprise the individual signals of measuring by the described fragment more than of described bending channel.
42. as each described method in the aforementioned claim, wherein said box comprises by fluid mode a plurality of measured zone connected in series, each measured zone is aimed at optical system and the light source that is arranged in the described shell, described method comprises makes described fluid sample flow through each measured zone in described a plurality of measured zone, and measures the light transmission by each measured zone of described a plurality of measured zone.
43. as each described method in the aforementioned claim, comprise: during whole analysis basically, at the entrance of described first measured zone of described box and be arranged on the non-zero pressure drop that applies substantial constant between the outlet in described the first measured zone downstream.
44. as each described method in the aforementioned claim, wherein said analyzer comprises a plurality of light sources, described a plurality of light source comprises the first light source and the secondary light source adjacent with described the first light source at least, wherein said the first light source is configured to make light by the first measured zone of described box, described secondary light source is configured to make light to pass through described box, second measured zone adjacent with described the first measured zone, described method comprises start described the first light source when described secondary light source does not start, unless and close described the first light source, otherwise do not start described secondary light source.
45. such as each described method in the aforementioned claim, comprise with the described a plurality of light sources of the mode sequence starting that once only starts a light source.
46. as each described method in the aforementioned claim, be included in the upper opaque material of piling up in part surface of the passage in described first measured zone of described box, and measure the light transmission by described opaque material.
47. such as each described method in the aforementioned claim, wherein said opaque material comprises metal.
48. such as each described method in the aforementioned claim, wherein said metal comprises silver.
49. such as each described method in the aforementioned claim, wherein form described opaque material by electroless deposition.
50. such as each described method in the aforementioned claim, wherein deposit described opaque material by electroless deposition at metallic colloid.
51. such as each described method in the aforementioned claim, wherein said metallic colloid comprises gold pairing antibody.
52. such as each described method in the aforementioned claim, wherein form described opaque material by making metallic solution flow through described passage.
53. such as each described method in the aforementioned claim, comprise the opacity of determining quantitatively described opaque material.
54. as each described method in the aforementioned claim, comprise by the absorbent material in the liquid containing zone absorbing fluid in the described box that wherein said liquid containing zone is communicated with described the first measured zone fluid.
55. as each described method in the aforementioned claim, comprise basically all absorption of fluids that will flow in the described box with liquid containing zone that described the first measured zone fluid is communicated with in, allow simultaneously all gas from the outlet effusion of described box.
56. such as each described method in the aforementioned claim, wherein said fluid sample comprises whole blood.
57. an equipment comprises:
The first assembly, it comprises the first passage that forms with the first material, described first passage comprises entrance, outlet and has at least one part greater than 200 microns cross sectional dimensions that between the entrance of described first passage and outlet the water vapor permeable rate of wherein said the first material is lower than about 0.05gmm/m 2D;
The second assembly, it comprises the second channel that forms with the second material, described second channel comprises entrance, outlet and have at least one part less than 200 microns cross sectional dimensions between the entrance of described second channel and outlet, wherein between the optical wavelength of 400nm and 800nm the optical transmittance of described the second material greater than 90%; And
Fluid connector, be used for connecting described first passage and described second channel by the fluid mode, described fluid connector comprises fluid path, described fluid path comprises fluid path entrance and fluid path outlet, wherein said fluid path entrance can connect by the fluid mode outlet of described first passage, and described fluid path outlet can connect by the fluid mode entrance of described second channel
Wherein said equipment is packaged as so that described fluid connector does not connect described first passage and described second channel by the fluid mode.
58. a device comprises:
The first assembly, comprise the first passage that forms and comprise at least one entrance and an outlet with the first material, described first passage comprises at least one part that has greater than 200 microns cross sectional dimensions, and the water vapor permeable rate of wherein said the first material is lower than about 0.05gmm/m 2D;
The second assembly, comprise the second channel that forms and comprise at least one entrance and an outlet with the second material, described second channel comprises at least one part that has less than 200 microns cross sectional dimensions, wherein between the optical wavelength of 400nm and 800nm the optical transmittance of described the second material greater than 90%;
Fluid connector, can be connected to described the first assembly and described the second assembly, described fluid connector comprises fluid path, described fluid path comprises fluid path entrance and fluid path outlet, wherein when connecting, described fluid path entrance is by being fluidically connected to the outlet of described first passage, and described fluid path outlet is by being fluidically connected to the entrance of described second channel, to allow described first passage to be communicated with fluid between the described second channel
Wherein, before using first, described first passage does not have fluid to be communicated with described second channel mutually, when using first, so that described first passage is communicated with the mutual fluid of described second channel.
59. such as each described device or equipment in the aforementioned claim, wherein said the first assembly and described the second assembly are smooth basically, and place adjacent to each other.
60. such as each described device or equipment in the aforementioned claim, wherein said the first assembly and described the second assembly are smooth basically, and a top that is placed on another.
61. as each described device or equipment in the aforementioned claim, wherein said the first assembly comprises the parts with the parts complementation of described the second assembly, is connected with nonfluid between described the second assembly thereby form described the first assembly.
62. such as each described device or equipment in the aforementioned claim, wherein said the first assembly integrally is connected each other with described the second assembly.
63. such as each described device or equipment in the aforementioned claim, wherein said the first assembly and described the second assembly reversibly are attached to one another.
64. such as each described device or equipment in the aforementioned claim, described at least one part of the described first passage of wherein said the first assembly is surrounded by described the second assembly basically, and/or described at least one part of the described second channel of described the second assembly is surrounded by described the first assembly basically.
65. such as each described device or equipment in the aforementioned claim, described at least one part of the described first passage of wherein said the first assembly is surrounded by the first cover plate that is not described the second assembly basically, and/or described at least one part of the described second channel of wherein said the second assembly is surrounded by the second cover plate that is not described the first assembly basically.
66. such as each described device or equipment in the aforementioned claim, wherein said the first cover plate and/or described the second cover plate are belts.
67. such as each described device or equipment in the aforementioned claim, wherein said the first material is different from described the second material.
68. such as each described device or equipment in the aforementioned claim, the water vapor permeable rate of wherein said the first material is at about 0.01gmm/m 2D and about 0.4gmm/m 2Between the d.
69. such as each described device or equipment in the aforementioned claim, the fusion temperature of wherein said the first material is higher than described the second material.
70. such as each described device or equipment in the aforementioned claim, the fusion temperature of wherein said the second material is lower than about 100 ° of C.
71. as aforementioned claim in each described device or equipment, wherein between the optical wavelength of 400nm and 800nm the optical transmittance of described the second material greater than 95%.
72. as aforementioned claim in each described device or equipment, wherein between the optical wavelength of 400nm and 800nm the optical transmittance of described the first material less than 10%.
73. such as each described device or equipment in the aforementioned claim, wherein said the first material comprises cyclic olefine copolymer.
74. such as each described device or equipment in the aforementioned claim, wherein said the second material comprises polystyrene, PMMA or cyclic olefine copolymer.
75. such as each described device or equipment in the aforementioned claim, the root mean square surface roughness of described at least one part of wherein said first passage is greater than about 5 microns, and the root mean square surface roughness of described at least one part of described second channel is less than about 5 microns.
76. such as each described device or equipment in the aforementioned claim, comprise the first reagent that is arranged in the described first passage, wherein at least one entrance and an outlet of described first passage are sealed before using first, thus with described the first reagent storage in described first passage.
77. such as each described device or equipment in the aforementioned claim, comprise the first reagent that is arranged in the described first passage, wherein at least one entrance and an outlet of described first passage are sealed before using first, thereby with described the first reagent storage at least one sky, at least one week or at least one moon in described first passage.
78. such as each described device or equipment in the aforementioned claim, wherein said the first reagent is liquid.
79. such as each described device or equipment in the aforementioned claim, comprise the second reagent that is arranged in the described second channel, wherein at least one entrance and an outlet of described second channel are sealed before using first, thus with described the second reagent storage in described second channel.
80. as each described device or equipment in the aforementioned claim, wherein will described the second reagent drying before using first and absorb the surface of described at least one part of described second channel.
81. such as each described device or equipment in the aforementioned claim, wherein said the second assembly comprises the conversion zone that is communicated with described second channel fluid.
82. such as each described device or equipment in the aforementioned claim, wherein said conversion zone comprises at least one bending channel zone.
83. such as each described device or equipment in the aforementioned claim, wherein said conversion zone comprises at least two bending channel zones connected in series.
84. such as each described device or equipment in the aforementioned claim, comprise alignment member, it is associated with described the first assembly or described the second assembly, one of them extension from described the first assembly or described the second assembly, and comprise structure and be arranged as the chamber that holds and engage described fluid connector, thereby with respect to described the first assembly or described the second assembly described connector is set with predetermined fixed configurations.
85. such as each described device or equipment in the aforementioned claim, wherein when described fluid connector was connected to described the first assembly or described the second assembly, described fluid connector was placed on the plane that is substantially perpendicular to described the first assembly and/or described the second assembly.
86. such as each described device or equipment in the aforementioned claim, wherein when described fluid connector is connected to described the first assembly or described the second assembly, described fluid connector is arranged on a side relative with another assembly of assembly.
87. such as each described device or equipment in the aforementioned claim, the fluid path of wherein said fluid connector has at least length of 2cm.
88. as each described device or equipment in the aforementioned claim, each in wherein said the first assembly and described the second assembly comprises that thickness is at least one part of 2.5mm at least.
89. such as each described device or equipment in the aforementioned claim, in wherein said the first assembly and described the second assembly each comprises that thickness is at least one part of 2.5mm at least, and in wherein said the first assembly and described the second assembly at least one comprises that thickness is less than at least one part of 2.5mm.
90. such as each described device or equipment in the aforementioned claim, wherein said the first assembly and described the second assembly form by injection molding, described at least one part of described first passage forms by the first injection tool, and described at least one part of described second channel forms by the second injection tool, and wherein said the first injection tool and described the second injection tool are made by distinct methods.
91. such as each described device or equipment in the aforementioned claim, wherein said the first injection tool is made by grinding or photoetching process.
92. such as each described device or equipment in the aforementioned claim, wherein said the second injection tool is made by grinding or photoetching process.
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